Imidazole derivatives as adenosine deaminase inhibitors

ABSTRACT

Imidazole compounds having adenosine deaminase inhibitory activity represented by the formula (I) wherein R1 is aryl or heterocyclic group which is optionally substituted with substituent(s); R 2  is lower alkyl; R 3  is hydroxy or protected hydroxy; -A- is lower alkylene; and —X—is —O— or —S—; provided that when then R1 is aryl which is substituted with substituent(s), or heterocyclic group which is optionally substituted with substituent(s), its prodrug, or their salt. The compounds are useful for treating and/or preventing diseases for which adenosine is effective.

TECHNICAL FIELD

[0001] This invention relates to novel imidazole compounds havingpharmacological activity, to a process for their production and to apharmaceutical composition containing the same.

BACKGROUND ART

[0002] Adenosine (Ado) is an endogenous purine nucleoside released bycells as part of the normal metabolic machinery. Ado has wide variety ofbiological activities, namely potent antiinflammatory andimmunosuppressive properties, protective effects in cardiovascular andcerebrovascular ischemia, anticonvulsant effects and modulation effectsof platelet aggregation, lipolysis, glycogenesis, blood flow andneurotransmission. Ado shows the biological activities by binding to itsreceptors anchored in the cell membrane. Therefore, it is the beneficialtreatment for many diseases to perform the pharmacological elevation ofextracellular Ado concentrations.

[0003] Adenosine deaminase (ADA) catalyzes an essentially irreversibledeamination of adenosine and deoxyadenosine to inosine and deoxyinosine,respectively. In the last 10 years, ADA, which was considered to becytosolic, has been found on the cell surface of many cells. Thus,blocking ADA activity with specific inhibitor is the potent way toelevate Ado concentrations in biological systems and the beneficialtreatment for many diseases.

[0004] Some compounds have been known to have inhibitory activity of ADA(J. Med. Chem. 27, 274-278, 1984; ibid. 31, 390-393, 1988; ibid. 34,1187-1192, 1991; ibid. 35, 4180-4184, 1992; ibid. 37, 305-308, 1994;ibid. 37, 3844-3849, 1994; WO98/02166).

[0005] Known imidazole compounds with pharmaceutical activity other thanADA inhibitory activity are described in U.S. Pat. No. 4,451,478 andWO97/26883.

[0006] Furthermore, some imidazole derivatives having ADA inhibitoryactivity have been reported, for example, as described in DrugDevelopement Research 28, 253-258, 1993.

DISCLOSURE OF THE INVENTION

[0007] This invention relates to novel imidazole compounds, which havepharmaceutical activity such as ADA inhibiting activity, to a processfor their production, to a pharmaceutical composition containing thesame, and to a use thereof.

[0008] One object of this invention is to provide the novel imidazolecompounds, which have an ADA inhibiting activity.

[0009] Another object of this invention is to provide a process forproduction of the imidazole compounds.

[0010] A further object of this invention is to provide a pharmaceuticalcomposition containing the imidazole compound as an active ingredient.

[0011] Still further object of this invention is to provide a use of theimidazole compound for manufacturing a medicament for treating orpreventing various diseases, or a method of treating or preventingvarious diseases by administering the imidazole compound in an effectiveamount to elevate adenosine concentration.

[0012] The imidazole compound of this invention can be represented bythe following formula (I):

[0013] wherein R¹ is aryl or heterocyclic group which is optionallysubstituted with substituent(s);

[0014] R² is lower alkyl;

[0015] R³ is hydroxy or protected hydroxy;

[0016] -A- is lower alkylene; and

[0017] —X— is —O— or —S—;

[0018] provided that when —X—is —O—, then R¹ is aryl which issubstituted with substituent(s), or heterocyclic group which isoptionally substituted with substituent(s), its prodrug, or their salt.

[0019] In the compound of formula (I), R¹ is preferably (1) aryloptionally substituted with substituent(s) selected from the groupconsisting of lower alkyl, halogen, optionally substituted aryl,optionally substituted heterocyclic group, lower alkoxy, and cyano, (2)condensed heterocyclic group optionally substituted with suitablesubstituent(s) selected from the group consisting of lower alkyl,optionally substituted aryl, and aryl(lower)alkyl, or (3) unsaturatedheteromonocyclic group containing 1 to 4 nitrogen atoms which isoptionally substituted with optionally substituted aryl. -A- ispreferably methylene or ethylene. R² is preferably methyl.

[0020] The compound (I), its prodrug, or their salt can be prepared bythe following processes. In the following formulae, compounds may beprodrugs or their salts.

[0021] Process 1

[0022] The compound (I) wherein —X— is —O—, and R³ is not hydroxy can beobtained by reacting a compound of formula (II)

R¹—OH  (II)

[0023] wherein R¹ is as defined above, with a compound of formula (III)

[0024] wherein R², R³, and -A- are as defined above, and X¹ is hydroxyor a leaving group (such as halogen, alkanesulfonyloxy, arylsulfonyloxy,and the like), provided that R³ is not hydroxy.

[0025] The reaction may be carried out in a manner such as the Mitsunobureaction or the modification thereof. This reaction can be preferablycarried out in the presence of di(lower)alkyl azodicarboxylate (e.g.,diethyl azodicarboxylate, etc.) and trialkyl or triarylphosphines (e.g.,triphenylphosphine, etc.) in a solvent, which does not adversely affectthe reaction, such as tetrahydrofuran, diethyl ether, or the like. Thereaction temperature is not critical and the reaction is usually carriedout under cooling to warming.

[0026] Alternatively, in the case where X¹ is a leaving group, thecompound (I) can also be produced by reacting the compound (III) withthe compound (II) in the presence of a base such as sodium hydride,potassium tert-butoxide, or potassium carbonate in a solvent such asN,N-dimethylformamide (DMF) from room temperature to 100° C.

[0027] Process 2

[0028] The compound (I) wherein —X— is —O—, and R³ is hydroxy can beobtained by reacting a compound of formula (I-1)

[0029] wherein R¹, R², and -A- are as defined above, and R′ is hydroxyprotective group, with a deprotecting agent.

[0030] The compound (I-1) can be reacted with a deprotecting agent suchas palladium hydroxide on carbon/cyclohexene, trimethylsilyl iodide, ortetra-n-butylammonium fluoride in a solvent, which does not adverselyaffect the reaction, such as ethanol, chloroform, or tetrahydrofuran.The reaction temperature is not critical and the reaction is usuallycarried out under cooling to warming.

[0031] Process 3

[0032] The compound (I) can be obtained by reacting a compound offormula (IV)

[0033] wherein R¹, R², R³, -A-, and —X— are as defined above, withaqueous ammonia solution.

[0034] The reaction can be carried out in a solvent, which does notadversely affect the reaction, such as methanol, 1,2-dimethoxyethane, orthe like from 50° C. to 120° C.

[0035] In the following, suitable examples of the definitions to beincluded within the scope of the invention are explained in detail.

[0036] The term “lower” means a group having 1 to 6 carbon atom(s),unless otherwise provided.

[0037] Suitable “lower alkyl” and lower alkyl moiety of “lower alkoxy”,“halo(lower)alkyl,” and “aryl(lower)alkyl” include a straight orbranched one such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl,tert-butyl, pentyl, hexyl, or the like, with methyl, ethyl, andtert-butyl being preferred.

[0038] Suitable “lower alkylene” may be straight or branched one having1 to 8 carbon atom(s), such as methylene, ethylene, trimethylene,tetramethylene, pentametylene, hexamethylene, or the like, withmethylene and ethylene being preferred.

[0039] Suitable “halogen” and halogen moiety of “halo(lower)alkyl”include fluorine, chlorine, bromine, or iodine.

[0040] Suitable “aryl” and aryl moiety of “aryl(lower)alkyl” includephenyl, naphthyl, tolyl, xylyl, fluorenyl, or the like, with phenyl,naphthyl, and fluorenyl being preferred.

[0041] Suitable “heterocyclic group” includes one containing at leastone heteroatom selected from the group consisting of nitrogen, sulfur,and oxygen atoms, and include saturated or unsaturated, monocyclic orpolycyclic heterocyclic group such as:

[0042] (1) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl,1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.], tetrazolyl [e.g.,1H-tetrazolyl, 2H-tetrazolyl, etc.], etc.;

[0043] (2) saturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 4 nitrogen atoms, for example,pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.;

[0044] (3) unsaturated, condensed heterocyclic group containing 1 to 5nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl,benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl,tetrazolopyridazinyl [e.g., tetrazolo[1,5-b]pyridazinyl, etc.], etc.;

[0045] (4) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing an oxygen atom, for example, pyranyl,furyl, etc.;

[0046] (5) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms, for example,thienyl, etc.;

[0047] (6) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl [e.g.,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.], etc.;

[0048] (7) saturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, for example, morpholinyl, etc.;

[0049] (8) unsaturated, condensed heterocyclic group containing 1 to 2oxygen atoms and 1 to 3 nitrogen atoms, for example, benzoxazolyl,benzoxadiazolyl, etc.;

[0050] (9) unsaturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolyl, thiadiazolyl [e.g.,1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.], etc.;

[0051] (10) saturated, 3 to 7-membered, preferably 5 or 6-memberedheteromonocyclic group containing 1 to 2 sulfur atoms and 1 to 3nitrogen atoms, for example, thiazolidinyl, etc.;

[0052] (11) unsaturated, condensed heterocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, benzothiazolyl,benzothiadiazolyl, etc.;

[0053] (12) unsaturated, condensed heterocyclic group containing 1 to 2sulfur atoms or 1 to 2 oxygen atoms, for example, benzo[b]thiophenyl,benzofuranyl, dibenzofuranyl, etc.; or the like.

[0054] Among the above, more preferable “heterocyclic group” isabove-mentioned (1), (3) (5), (6), (7), (8), (9), (11), and (12), inwhich the most preferable one is pyrrolyl (e.g., 1-pyrrolyl, etc.),pyridyl (e.g., 2-pyridyl, 3-pyridyl, etc.), indolyl (e.g.,1H-indol-5-yl, etc.), benzimidazolyl (e.g., 1H-benzimidazol-2-yl, etc.),quinolyl (e.g., 2-quinolyl, 6-quinolyl, etc.), isoquinolyl (e.g.,3-isoquinolyl, 7-isoquinolyl, etc.), thienyl (e.g., 2-thienyl, etc.),morpholinyl (e.g., 4-morpholinyl, etc.), benzoxazolyl (e.g.,2-benzoxazolyl, 6-benzoxazolyl, etc.), thiazolyl (e.g., 4-thiazolyl,etc.), benzothiazolyl (e.g., 5-benzothiazolyl, etc.), benzo[b]thiophenyl(e.g., 2-benzo[b]thiophenyl, etc.), benzofuranyl (e.g., 2-benzofuranyl,etc.), or dibenzofuranyl (e.g., 2-dibenzofuranyl, etc.).

[0055] Suitable “protected hydroxy” includes lower alkoxy optionallysubstituted with aryl (e.g., benzyloxy, etc.); acyloxy; ortri(lower)alkylsilyloxy (i.e., trimethylsilyloxy,tert-butyldimethylsilyloxy, etc.); or the like.

[0056] Suitable hydroxy protective groups in the protected hydroxy groupinclude lower alkyl optionally substituted with aryl; acyl;tri(lower)alkylsilyl (i.e., trimethylsilyl, tert-butyldimethyl-silyl,etc.); or the like. Here, suitable “acyl” includes acetyl,trifluoroacetyl, or the like.

[0057] Suitable “leaving group” includes halogen, acyloxy (e.g.,acetyloxy, trifluoroacetyloxy, etc.), lower alkylsulfonyloxy (e.g.,methanesulfonyloxy, etc.), triarylphosphinoxy (e.g., —O—P⁺ (C₆H₅)₃,etc.), or the like.

[0058] Suitable substituent(s) of “optionally substituted aryl” and“optionally substituted heterocyclic group” include lower alkyl,halo(lower)alkyl, lower alkoxy, halogen, aryl, aryl(lower)alkyl, cyano,or the like.

[0059] The term “optionally substituted aryl” means aryl which isoptionally substituted with one or more substituent(s) selected from thegroup consisting of lower alkyl, halo(lower)alkyl, lower alkoxy,halogen, cyano, and the like.

[0060] Examples of the “optionally substituted aryl” includeunsubstituted aryl such as phenyl or the like; haloaryl such as4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl,3,5-dichlorophenyl, or the like; lower alkylaryl such as 4-methylphenyl,or the like; lower alkoxyaryl such as 3-methoxyphenyl, 4-methoxyphenyl,or the like; halo(lower)alkylaryl such as 4-(trifluoromethyl)phenyl orthe like; cyanoaryl such as 4-cyanophenyl, or the like; etc.

[0061] The term “optionally substituted heterocyclic group” meansheterocyclic group which is optionally substituted with one or moresubstituent(s) selected from the group consisting of lower alkyl, loweralkoxy, halogen, aryl, aryl(lower)alkyl, and the like.

[0062] Examples of the “optionally substituted heterocyclic group”include unsubstituted heterocyclic group such as 1H-benzimidazol-2-yl,2-thienyl, 4-morpholinyl, 2-benzoxazolyl, 1-benzothien-2-yl,2-benzofuranyl, 1H-pyrrol-1-yl, or the like; heterocyclic groupsubstituted with lower alkyl, such as 5-methyl-2-thienyl or the like;heterocyclic group substituted with lower alkoxy, such as6-methoxy-3-pyridyl or the like; heterocyclic group substituted withhalogen, such as 5-chloro-2-thienyl, 6-chloro-3-pyridyl, or the like;heterocyclic group substituted with aryl, such as 2-phenylthiazol-4-ylor the like; heterocyclic group substituted with aryl(lower)alkyl, suchas 2-benzylthiazol-4-yl or the like.

[0063] Suitable salts of the compounds of the present invention arepharmaceutically acceptable conventional non-toxic salts and can be anorganic acid addition salt (e.g., formate, acetate, trifluoroacetate,maleate, tartarate, oxalate, methanesulfonate, benzenesulfonate,toluenesulfonate, etc.),. an inorganic acid addition salt (e.g.,hydrochloride, hydrobromide, sulfate, phosphate, etc.), a salt with anamino acid (e.g., aspartic acid salt, glutamic acid salt, etc.), or thelike.

[0064] The “prodrug” means the derivatives of compounds of the presentinvention having a chemically or metabolically degradable group, whichbecomes pharmaceutically active after biotransformation.

[0065] The compounds of formula (I) may contain one or more asymmetriccenters and thus they can exist as enantiomers or diastereoisomers.Furthermore certain compounds of formula (I) which contain alkenylgroups may exist as cis- or trans-isomers. In each instance, theinvention includes both mixtures and separate individual isomers.

[0066] The compounds of the formula (I) may also exist in tautomericforms and the invention includes both mixtures and separate individualtautomers.

[0067] The compound of the formula (I) and its salt can be in a form ofa solvate, which is included within the scope of the present invention.The solvate preferably include a hydrate and an ethanolate.

[0068] Also included in the scope of invention are radiolabelledderivatives of compounds of formula (I) which are suitable forbiological studies.

[0069] The compound of the present invention can be purified by anyconventional purification methods employed for purifying organiccompounds, such as recrystallization, column chromatography, thin-layerchromatography, high-performance liquid chromatography, and the like.The compounds can be identified by conventional methods such as NMRspectrometry, mass spectrometry, IR spectrometry, elemental analysis,measurement of melting point, and the like.

[0070] The compound (I), its prodrug, or their salt can be administeredalone or in the form of a mixture, preferably, with a pharmaceuticalvehicle or carrier.

[0071] The active ingredient of this invention can be used in the formof a pharmaceutical preparation, for example, in solid, semisolid, orliquid form, which contains a compound (I), as an active ingredient, inadmixture with an organic or inorganic carrier or excipient suitable fororal, external (topical), enteral, intravenous, intramuscular,parenteral, or intramucous applications. The active ingredient can beformulated, for example, with the conventional non-toxic,pharmaceutically acceptable carriers for ointment, cream, plaster,tablets, pellets, capsules, suppositories, solution (saline, forexample), emulsion, suspension (olive oil, for example), aerosols,pills, powders, syrups, injections, troches, cataplasms, aromaticwaters, lotions, buccal tablets, sublingual tablets, nasal drops, andany other form suitable for use. The carriers which can be used arewater, wax, glucose, lactose, gum acacia, gelatin, mannitol, starchpaster, magnesium trisilicate, talc, corn starch, keratin, paraffin,colloidal silica, potato starch, urea, and other carriers suitable foruse in manufacturing preparations, in solid, semisolid, or liquid form,and in addition, auxiliary, stabilizing, thickening, and coloring agentsand perfumes may be used. The active compound is included in apharmaceutical composition in an effective amount sufficient to producethe desired effect upon the process or condition of the diseases.

[0072] The active ingredient can be formulated into, for example,preparations for oral application, preparations for injection,preparations for external application, preparations for inhalation,preparations for application to mucous membranes, etc.

[0073] Mammals which may be treated by the present invention includelivestock mammals such as cows, horses, etc., domestic animals such asdogs, cats, rats, etc., and humans, and preferably humans.

[0074] While the dosage of therapeutically effective amount of thecompound (I) will vary depending upon the age and condition of eachindividual patient, an average single dose to a human patient of about0.01 mg, 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg, and 1000 mgof the compound (I) may be effective for treating the above-mentioneddiseases. In general, amounts between 0.01 mg/body and about 1,000mg/body may be administered per day.

[0075] An ADA inhibitor, such as the compound (I) or itspharmaceutically acceptable salts of this invention, possesses ADAinhibiting activity and are thus useful in immunomodulation, especiallyimmunosuppression, antiinflammation and treatment and prevention ofvarious diseases for which Ado is effective. Examples of the diseasesare as follows:

[0076] a) Autoimmune diseases and inflammatory conditions, e.g., variouspains collagen diseases, autoimmune diseases, various immunity diseases,and the like in human beings or animals, and more particularly for thetreating and/or preventing inflammation and pain in joint and muscle(e.g., rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis,gouty arthritis, etc.), inflammatory skin condition (e.g., sunburn,eczema, etc.), inflammatory eye condition (e.g., conjunctivitis, etc.),lung disorder in which inflammation is involved (e.g., asthma,bronchitis, pigeon fancier's disease, farmer's lung, etc.), condition ofthe gastrointestinal tract associated with inflammation (e.g., aphthousulcer, Crohn's disease, atrophic gastritis, ulcerative colitis, coeliacdisease, regional ileitis, irritable bowel syndrome, etc.), gingivitis,(inflammation, pain and tumescence after operation or injury), pyrexia,pain and other conditions associated with inflammation, systemic lupuserythematosus, scleroderma, polymyositis, polychondritis, periarteritisnodosa, ankylosing spondylitis, inflammatory chronic renal condition(e.g., nephrotic syndrome, glomerulonephritis, membranous nephritis,etc.), acute nephritis, rheumatic fever, Sjogren's syndrome, Behcetdisease, thyroiditis, type I diabetes, dermatomyositis, chronic activehepatitis, acute hepatitis, myasthenia gravis, idiopathic sprue, Grave'sdisease, multiple sclerosis, primary billiary cirrhoris, Reiter'ssyndrome, autoimmune hematological disorders (e.g., hemolytic anemia,pure red cell anemia, idiopathic thrombocytopenia; aplastic anemia,etc.), myasthenia gravis, uveitis, contact dermatitis, psoriasis,Kawasaki disease, sarcoidosis, Wegner's granulomatosis, Hodgkin'sdisease, or the like;

[0077] b) Organ or tissue allo- or xeno-transplant rejection, e.g.,kidney, liver, heart, lung, combined heart-lung, bone marrow, isletcells, pancreatic, skin, chromaffin or dopamine producing cells, smallbowel, or corneal transplantation. Treating and/or preventinggraft-versus-host disease, such as occurs following bone marrowtransplantation;

[0078] c) Chronic pain (e.g., cancer pain, diabetic neuropathy, etc);

[0079] d) Various leukemias, including virus induced or various inducedlymphomas; and

[0080] e) Diseases that arise from, or are aggravated by, insufficientblood flow through a particular organ or portion thereof, e.g., heartattacks or strokes, the microvascular disease of diabetes mellitus,atherosclerosis, or events resulting in a less prolonged loss of bloodflow (e.g., angina pectoris, transient ischemic attacks, bowel ischemia,kidney ischemia, intermittant claudication of skeletal muscle, migraineheadaches, Raynaud's phenomenon), or the like.

[0081] An ADA inhibitor, such as the compound (I) or itspharmaceutically acceptable salt of this invention, is useful forprotection against the progression of glomerulosclerosis by suppressingglomerular hypertension and hyperfiltration, and thus useful fortreatment and/or prevention of glomerulosclerosis.

[0082] An ADA inhibitor, such as the compound (I) or itspharmaceutically acceptable salt of this invention, is useful forcomplementing the defect of an IL-2 inhibitor, such as FK506,cyclosporin, or the like, in immunosuppresive effects. Thus, thecombination use of the two compounds enables treatment and prevention ofvarious diseases and conditions in need of immunosuppression.

[0083] Any patents, patent applications, and publications cited hereinare incorporated by reference.

[0084] In order to illustrate the usefulness of the object compound (I),the pharmacological test data of the compound (I) are shown in thefollowing.

[0085] Adenosine Deaminase (ADA) Enzyme Assay

[0086] Test Compound:

[0087]1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(Example 20)

[0088]1-{(2S,3R)-2-hydroxy-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(Example 32)

[0089]1-[(2S,3R)-2-hydroxy-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(Example 49)

[0090]1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxamide(Example 76)

[0091]1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxamide(Example 78)

[0092] Test Method:

[0093] The reaction velocity (V) is measured by a change in absorbanceat 265 nm (A265) resulting from the deamination of adenosine. Human ADAwas expressed and purified from ADA-deficient bacterial strain. Reactionmixtures of a total volume of 200 μl contained 0.16 μg/ml of ADA and 0.1mM of adenosine and test compound in 10 mM phosphate buffer saline (pH7.4). The reaction was started by addition of ADA to a mixture ofadenosine and test compound. The reaction was followed at roomtemperature by recording decrease in A265 for 3 minutes in SPECTRAmax250 (Molecular Devices, USA) to automatically calculate V_(max).Inhibitory potency of test compound was expressed as IC₅₀ value, thedrug concentration required to produce 50% inhibition of V_(max) incomparison to vehicle treatment. Results: Test Compound IC₅₀ (nM)Example 20 <20 Example 32 <20 Example 49 <20 Example 76 <20 Example 78<20

BRIEF DESCRIPTION OF THE DRAWINGS

[0094]FIG. 1 shows chemical formulae of compound (1) to compound (8).

[0095]FIG. 2 shows chemical formulae of compound (9) to compound (16).

[0096]FIG. 3 shows chemical formulae of compound (17) to compound (24).

[0097]FIG. 4 shows chemical formulae of compound (25) to compound (32).

[0098]FIG. 5 shows chemical formulae of compound (33) to compound (40).

[0099]FIG. 6 shows chemical formulae of compound (41) to compound (48).

[0100]FIG. 7 shows chemical formulae of compound (49) to compound (56).

[0101]FIG. 8 shows chemical formulae of compound (57) to compound (64).

[0102]FIG. 9 shows chemical formulae of compound (65) to compound (72).

[0103]FIG. 10 shows chemical formulae of compound (73) to compound (80).

[0104]FIG. 11 shows chemical formulae of compound (81) to compound (88).

[0105]FIG. 12 shows chemical formulae of compound (89) to compound (96).

[0106]FIG. 13 shows chemical formulae of compound (97) to compound(104).

BEST MODE FOR CARRYING OUT THE INVENTION

[0107] The following Preparation and Examples are given for the purposeof illustrating the present invention in detail, but are not to beconstrued to limit the scope of the present invention.

EXAMPLE 1

[0108] Under N₂, to a solution of 6-hydroxyquinoline (43 mg, 0.296 mmol)in DMF (3 ml) was added potassium carbonate (82 mg, 0.593 mmol) at roomtemperature. The reaction mixture was stirred for 30 minutes.1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamidewas added and the resulting mixture was stirred for 6 h at 70° C. Thereaction mixture was poured into water (30 ml) and extracted with ethylacetate. The organic layer was washed with brine, dried (sodium sulfate)and evaporated in vacuo. The residue was purified by silica gel (8 g)chromatography eluting with chloroform/methanol (100:1 to 30:1) to give1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(1) (62.5 mg, 48.9%).

[0109] IR (KBr, cm⁻¹): 3600-2800, 1664, 1597, 1230, 1110

[0110] NMR (CDCl₃, δ): 1.21 (3H, d, J=6 Hz), 2.15-2.75 (2H, m),3.60-4.20 (3H, m), 4.30-4.50 (2H, m), 4.67 (1H, d, J=12 Hz), 5.36 (1H,brs), 6.91 (1H, d, J=3 Hz), 6.92 (1H, brs), 7.20-7.40 (7H, m), 7.46 (1H,s), 7.70 (1H, s), 7.99 (2H, d, J=9 Hz), 8.77 (1H, dd, J=4.2 Hz)

[0111] MS: 431 (M+H)⁺

[0112] [α]_(D) ^(22.5)=+63.50° (C=0.50, EtOH)

EXAMPLE 2

[0113] To a solution of1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(58 mg, 0.135 mmol) in cyclohexene (2.5 ml) and ethanol (5 ml) was added20% palladium hydroxide on carbon (50 mg). The resulting mixture wasstirred at reflux for 8 h. After cooling to room temperature, themixture was filtered through Celite and washed with ethanol. Thefiltrate was concentrated in vacuo and then the residue was purified bysilica gel (1.5 g) chromatography eluted with chloroform/methanol (50:1to 10:1) to give1-[(2S,3R)-2-hydroxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(2) (39.8 mg, 86.8%).

[0114] IR (KBr, cm⁻¹): 3700-2800, 1664, 1595, 1232, 1120

[0115] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.20-2.65 (2H, m),3.65-4.40 (4H, m), 5.21 (1H, d, J=5 Hz), 7.03 (1H, brs), 7.15-7.55 (4H,m), 7.72 (1H, s), 7.78 (1H, s), 7.90 (1H, d, J=9 Hz), 8.19 (1H, d, J=8Hz), 8.71 (1H, dd, J=4.2 Hz)

[0116] MS: 341 (M+H)⁺

EXAMPLE 3

[0117] To a stirred mixture of 3,4-dichlorophenol (129 mg, 0.791 mmol),1-[(2S,3R)-2-benzyloxy-5-hydroxy-3-pentyl]imidazole-4-carboxamide (80mg, 0.264 mmol), and triphenylphosphine (90 mg, 0.343 mmol) intetrahydrofuran (5 ml) was added dropwise diethyl azodicarboxylate (59.7mg, 0.343 mmol) at ice-bath temperature. After the mixture was stirredfor 2 h at room temperature, the solvent was removed in vacuo. Theresidue was purified by silica gel (10 g) chromatography eluting withchloroform/methanol (100:1 to 30:1) to give a mixture (120.6 mg, 102%)of1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide(3) and by-products. This material was used without furtherpurification.

[0118] IR (KBr, cm⁻¹): 3600-2800, 1664, 1593, 1232, 1124

[0119] NMR (CDCl₃, δ): 1.17 (3H, d, J=6 Hz), 2.05-2.70 (2H, m),3.40-4.00 (3H, m), 4.29 (1H, m), 4.42 (1H, d, J=12 Hz), 4.65 (1H, d,J=12 Hz), 5.39 (1H, brs), 6.63 (1H, dd, J=9.3 Hz), 6.88 (1H, d, J=3 Hz),6.92 (1H, brs), 7.10-7.50 (7H, m), 7.65 (1H, s)

[0120] MS: 448 (M+H)⁺ (³⁵Cl×2), 450 (M+H)⁺ (³⁵Cl-³⁷Cl), 452 (M+H)⁺(³⁷Cl×2)

EXAMPLE 4

[0121] To an ice cooled solution of1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenyloxy)-3-pentyl]imidazole-4-carboxamide(59.5 mg, 0.133 mmol) in chloroform (5 ml) was added trimethylsilyliodide (34.5 mg, 0.173 mmol). After 3 minutes, the ice bath was removed,and then stirred at room temperature overnight. The reaction wasquenched by addition of methanol. This mixture was extracted with ethylacetate, and the extracts were washed with brine, dried (sodium sulfate)and evaporated in vacuo. The residue was purified by silica gel (2.5 g)chromatography eluting with chloroform/methanol (50:1 to 10:1) to give1-[(2S,3R)-5-(3,4-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(4) (40.4 mg, 85.0%) as a white amorphous solid.

[0122] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1234, 1126

[0123] NMR (DMSO-d₆, δ): 0.91 (3H, d, J=6 Hz), 2.05-2.55 (2H, m),3.50-4.25 (4H, m), 5.18 (1H, d, J=5 Hz), 6.88 (1H, dd, J=9.3 Hz), 7.02(1H, brs), 7.15 (1H, d, J=3 Hz), 7.24 (1H, brs), 7.48 (1H, d, J=9 Hz),7.69 (1H, s), 7.73 (1H, s)

[0124] MS: 358 (M+H)⁺ (³⁵Cl×2), 360 (M+H)⁺ (³⁵Cl-³⁷Cl), 362 (M+H)⁺(³⁷Cl×2)

EXAMPLE 5

[0125] This compound was prepared by a similar procedure to that ofExample 3.

[0126]1-[(2S,3R)-2-benzyloxy-5-(2-dibenzofuranyloxy)-3-pentyl]imidazole-4-carboxamide(5).

[0127] NMR (CDCl₃, δ): 1.20 (3H, d, J=6 Hz), 2.10-2.70 (2H, m) 3.55-4.10(3H, m), 4.30-4.50 (2H, m), 4.66 (1H, d, J=12 Hz), 5.36 (1H, brs), 6.93(1H, brs), 6.94 (1H, dd, J=9.3 Hz), 7.15-7.60 (11H, m), 7.71 (1H, s),7.83 (2H, d, J=8 Hz)

[0128] MS: 470 (M+H)+

EXAMPLE 6

[0129] This compound was prepared by a similar procedure to that ofExample 2.

[0130]1-[(2S,3R)-5-(2-dibenzofuranyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(6).

[0131] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1234, 1174

[0132] NMR (DMSO-d₆, δ): 1.00 (3H, d, J=6 Hz), 2.20-2.65 (2H, m)3.60-4.50 (4H, m), 5.30 (1H, br), 7.01 (1H, dd, J=9.3 Hz), 7.25-7.80(7H, m), 8.00 (1H, s), 8.09 (1H, d, J=8 Hz), 8.31 (1H, brs)

[0133] MS: 380 (M+H)⁺

EXAMPLE 7

[0134] This compound was prepared by a similar procedure to that ofExample 3.

[0135]1-[(2S,3R)-2-benzyloxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide(7).

[0136] NMR (CDCl₃, δ): 1.18 (3H, d, J=6 Hz), 2.10-2.75 (2H, m), 2.80(3H, s), 3.55-4.10 (3H, m), 4.30-4.50 (2H, m), 4.65 (1H, d, J=12 Hz),5.34 (1H, brs), 6.88 (1H, dd, J=9.2 Hz), 6.91 (1H, brs), 7.10-7.40 (6H,m), 7.45 (1H, s), 7.64 (1H, d, J=9 Hz), 7.67 (1H, s)

[0137] MS: 448 (M+H)⁺ (³⁵Cl×2), 450 (M+H)⁺ (³⁵Cl-³⁷Cl), 452 (M+H)⁺(³⁷Cl×2)

EXAMPLE 8

[0138] This compound was prepared by a similar procedure to that ofExample 2.

[0139]1-[(2S,3R)-2-hydroxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide(8).

[0140] IR (KBr, cm⁻¹): 3700-2800, 1658, 1604, 1454, 1323, 1167, 1082,1022

[0141] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m), 2.75(3H, s), 3.55-4.30 (4H, m), 5.18 (1H, d, J=5 Hz) 6.96 (1H, dd, J=9.2Hz), 7.02 (1H, brs), 7.24 (1H, brs), 7.36 (1H, d, J=2 Hz), 7.70 (1H, s),7.75 (1H, s), 7.85 (1H, d, J=9 Hz)

[0142] MS: 383 (M−H)⁻, 385 (M+H)⁺

EXAMPLE 9

[0143] This compound was prepared by a similar procedure to that ofExample 3.

[0144]1-[(2S,3R)-2-benzyloxy-5-(2-fluorenyloxy)-3-pentyl]imidazole-4-carboxamide(9).

[0145] IR (KBr, cm⁻¹): 3600-2800, 1664, 1604, 1259, 1107

[0146] NMR (CDCl₃, δ): 1.19 (3H, d, J=6 Hz), 2.05-2.70 (2H, m),3.50-4.10 (5H, m), 4.30-4.50 (2H, m), 4.65 (1H, d, J=12 Hz), 5.36 (1H,brs), 6.82 (1H, dd, J=8.2 Hz), 6.95 (1H, brs), 6.97 (1H, d, J=2 Hz),7.18-7.78 (12H, m)

[0147] MS: 468 (M+H)⁺

[0148] [α]_(D) ^(22.8)=+87.30° (C=0.50, EtOH)

EXAMPLE 10

[0149] This compound was prepared by a similar procedure to that ofExample 2.

[0150]1-[(2S,3R)-5-(2-fluorenyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(10).

[0151] IR (KBr, cm⁻¹): 3600-2800, 1657, 1583, 1263, 1109

[0152] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.55-4.30 (6H, m), 5.19 (1H, d, J=4 Hz), 6.88 (1H, dd, J=8.2 Hz), 7.02(1H, brs), 7.09 (1H, d, J=2 Hz) 7.10-7.40 (3H, m), 7.51 (1H, d, J=8 Hz),7.60-7.80 (4H, m)

[0153] MS: 378 (M+H)⁺

EXAMPLE 11

[0154] This compound was prepared by a similar procedure to that ofExample 3.

[0155]1-[(2S,3R)-2-benzyloxy-5-(2,3-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide(11).

[0156] IR (KBr, cm⁻¹): 3600-2800, 1672, 1265, 1090, 1057

[0157] NMR (CDCl₃, δ): 1.21 (3H, d, J=6 Hz), 2.05-2.75 (2H, m) 3.40-4.20(3H, m), 4.40-4.60 (2H, m), 4.65 (1H, d, J=12 Hz), 5.35 (1H, brs), 6.65(1H, dd, J=6.4 Hz), 6.91 (1H, brs), 7.00-7.40 (7H, m), 7.46 (1H, s),7.68 (1H, s)

[0158] MS: 448 (M+H)⁺ (³⁵Cl×2)

[0159] [α]D ^(22.8)=+100.90° (C=0.50, EtOH)

EXAMPLE 12

[0160] This compound was prepared by a similar procedure to that ofExample 4.

[0161]1-[(2S,3R)-5-(2.3-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(12).

[0162] IR (KBr, cm⁻¹): 3600-2800, 1658, 1585, 1450, 1267, 1057, 1028

[0163] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.65 (2H, m)3.60-4.30 (4H, m), 5.20 (1H, d, J=5 Hz), 6.90-7.40 (5H, m), 7.66 (1H,s), 7.73 (1H, s)

[0164] MS: 358 (M+H)⁺ (³⁵Cl×2), 360 (M+H)⁺ (³⁵Cl-³⁷Cl)

EXAMPLE 13

[0165] This compound was prepared by a similar procedure to that ofExample 3.

[0166]1-[(2S,3R)-2-benzyloxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide(13).

[0167] IR (KBr, cm⁻¹): 3600-2800, 1662, 1590, 1207

[0168] NMR (CDCl₃, δ): 1.20 (3H, d, J=6 Hz), 2.15-2.75 (2H, m),3.65-4.50 (5H, m), 4.67 (1H, d, J=12 Hz), 5.37 (1H, brs), 6.92 (1H,brs), 7.06 (1H, d, J=2 Hz), 7.20-7.45 (6H, m), 7.47 (1H, s), 7.57 (1H,d, J=6 Hz), 7.60 (1H, s), 7.72 (1H, d, J=9 Hz), 9.09 (1H, s)

[0169] MS: 431 (M+H)⁺

EXAMPLE 14

[0170] This compound was prepared by a similar procedure to that ofExample 2.

[0171]1-[(2S,3R)-2-hydroxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide(14).

[0172] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1267, 1207, 1142, 1092

[0173] NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.20-2.65 (2H, m),3.70-4.40 (4H, m), 5.22 (1H, brs), 7.07 (1H, brs), 7.20-7.50 (3H, m),7.70-7.85 (3H, m), 7.90 (1H, d, J=9 Hz), 8.37 (1H, d, J=6 Hz), 9.18 (1H,s)

[0174] MS: 341 (M+H)⁺

[0175] Preparation 1

[0176] To a solution of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate(1.0 g, 2.8 mmol) in methanol (15 ml) was added aqueous 28% NH₃ solution(15 ml). And the mixture was heated at 100° C. in a sealed steel tubefor 15 h. After cooling, the reaction mixture was concentrated in vacuo.The residue was purified by silica gel (35 g) chromatography elutingwith chloroform/methanol (25:1 to 15:1) to give1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxamide(769.5 mg, 83.8%) as a white amorphous solid.

[0177] IR (KBr, cm⁻¹): 3600-2800, 1664, 1604, 1417, 1261, 1143, 1092,1058

[0178] NMR (DMSO-d₆, δ) 0.00 (3H, s), 0.03 (3H, s), 0.86 (9H, s), 0.93(3H, d, J=6 Hz), 1.80-2.15 (2H, m), 2.95-3.45 (2H, m), 3.90-4.25 (2H,m), 4.55 (1H, t, J=5 Hz), 7.02 (1H, brs), 7.25 (1H, brs), 7.64 (1H, s),7.67 (1H, s)

[0179] MS: 327 (M−H)⁻

EXAMPLE 15

[0180] This compound was prepared by a similar procedure to that ofExample 3.

[0181]1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(15).

[0182] NMR (CDCl₃, δ): 0.05 (3H, s), 0.08 (3H, s), 0.93 (9H, s), 1.11(3H, d, J=6 Hz), 2.10-2.70 (2H, m), 3.65-4.35 (4H, m), 5.35 (1H, brs),6.90 (1H, brs), 6.95 (1H, d, J=2 Hz), 7.09 (1H, dd, J=9.2 Hz), 7.35-7.80(5H, m), 7.90 (1H, s)

[0183] MS: 532 (M+H)⁺ (⁷⁹Br), 534 (M+H)⁺ (⁸¹Br)

EXAMPLE 16

[0184] To an ice cooled solution of1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(120 mg, 0.225 mmol) in THF (5 ml) was added dropwise 1.0 Mtetra-n-butylammonium fluoride in THF (338 μl). After the addition wascompleted, the reaction mixture was stirred at ice-bath temperature for2 hours. The reaction was quenched by addition of 25% aqueous AcONH₄ (5ml) and H₂O (10 ml) The resulting mixture was stirred for severalminutes and then extracted with ethyl acetate (30 ml). The organic layerwas washed with brine, dried (sodium sulfate) and concentrated underreduced pressure. The residue was purified by silica gel (4 g) columnchromatography eluting with chloroform/methanol (100:1 to 20:1) to give1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(16) (58.6 mg, 62.2%) as a white solid.

[0185] IR (KBr, cm⁻¹): 3600-2800, 1655, 1593, 1498, 1261, 1207, 1126,1086

[0186] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.65 (2H, m),3.60-4.35 (4H, m), 5.20 (1H, d, J=5 Hz), 7.02 (1H, brs), 7.10-7.35 (3H,m), 7.54 (1H, dd, J=9.2 Hz), 7.60-7.90 (4H, m), 8.09 (1H, d, J=2 Hz)

[0187] MS: 418 (M+H)⁺ (⁷⁹Br), 420 (M+H)⁺ (⁸¹Br)

EXAMPLE 17

[0188] This compound was prepared by a similar procedure to that ofExample 15.

[0189]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dimethylphenoxy)-3-pentyl]imidazole-4-carboxamide(17).

[0190] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.90 (9H, s), 1.09(3H, d, J=6 Hz), 2.00-2.60 (8H, m), 3.40-4.30 (4H, m), 5.32 (1H, brs),6.53 (1H, dd, J=8.3 Hz), 6.60 (1H, d, J=3 Hz), 6.93 (1H, brs), 6.98 (1H,d, J=8 Hz), 7.41 (1H, s), 7.62 (1H, s)

[0191] MS: 432 (M+H)⁺

EXAMPLE 18

[0192] This compound was prepared by a similar procedure to that ofExample 16.

[0193]1-[(2S,3R)-5-(3,4-dimethylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(18).

[0194] IR (KBr, cm⁻¹): 3600-2800, 1660, 1599, 1500, 1412, 1248, 1119,1090, 1053

[0195] NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.00-2.55 (8H, m),3.40-4.30 (4H, m), 5.16 (1H, d, J=5 Hz), 6.55 (1H, dd, J=8, 2.5 Hz),6.64 (1H, d, J=2.5 Hz), 6.97 (1H, d, J=8 Hz), 7.02 (1H, brs), 7.24 (1H,brs), 7.67 (1H, s) 7.71 (1H, s)

[0196] MS: 318 (M+H)⁺

EXAMPLE 19

[0197] This compound was prepared by a similar procedure to that ofExample 15.

[0198]1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(19).

[0199] NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (4H, m), 5.36 (1H, brs),6.70-7.05 (3H, m), 7.10-7.75 (9H, m)

[0200] MS: 480 (M+H)⁺

EXAMPLE 20

[0201] This compound was prepared by a similar procedure to that ofExample 16.

[0202]1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(20).

[0203] IR (KBr, cm⁻¹): 3600-2800, 1658, 1595, 1473, 1415, 1238 1088

[0204] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.60-4.35 (4H, m), 5.18 (1H, d, J=5 Hz), 6.75-750 (9H, m), 7.55-7.85(4H, m)

[0205] MS: 366 (M+H)⁺

EXAMPLE 21

[0206] This compound was prepared by a similar procedure to that ofExample 15.

[0207]1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(21).

[0208] NMR (CDCl₃, δ): −0.06 (3H, s), 0.00 (3H, s), 0.87 (9H, s) 0.93(3H, d, J=6 Hz), 1.85-2.55 (2H, m), 3.30-4.20 (4H, m), 5.30 (1H, brs),6.80-7.10 (3H, m), 7.15-7.75 (9H, m)

[0209] MS: 480 (M+H)⁺

EXAMPLE 22

[0210] This compound was prepared by a similar procedure to that ofExample 16.

[0211]1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(22).

[0212] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1479, 1427, 1261, 1234,1122, 1088, 1059

[0213] NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 1.95-2.50 (2H, m),3.40-4.10 (4H, m), 5.13 (1H, d, J=5 Hz), 6.85-7.10 (3H, m), 7.15-7.70(10H, m)

[0214] MS: 366 (M+H)⁺

EXAMPLE 23

[0215] This compound was prepared by a similar procedure to that ofExample 15.

[0216]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide(23).

[0217] IR (KBr, cm⁻¹): 3600-2800, 1666, 1591, 1261, 1099

[0218] NMR (CDCl₃, δ): 0.01 (3H, s), 0.06 (3H, s), 0.89 (9H, s), 1.09(3H, d, J=6 Hz), 2.10-2.70 (2H, m), 3.90-4.50 (4H, m), 5.34 (1H, brs),6.90 (1H, brs), 6.92 (1H, s), 7.30-7.75 (5H, m), 7.87 (1H, d, J=8 Hz),8.90 (1H, s)

[0219] MS: 455 (M+H)⁺

EXAMPLE 24

[0220] This compound was prepared by a similar procedure to that ofExample 16.

[0221]1-[(2S,3R)-2-hydroxy-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide(24).

[0222] IR (KBr, cm⁻¹): 3600-2800, 1660, 1591, 1450, 1267, 1234, 1130,1090, 1051

[0223] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.15-2.60 (2H, m)3.65-4.35 (4H, m), 5.18 (1H, d, J=5 Hz), 7.03 (1H, brs), 7.11 (1H, s),7.25 (1H, brs), 7.35-7.85 (5H, m), 8.00 (1H, d, J=8 Hz), 9.00 (1H, s)

[0224] MS: 341 (M+H)⁺

[0225] Preparation 2

[0226] Under N₂, to a suspension of benzyltriphenylphosphonium bromide(980 mg, 2.26 mmol) in acetonitrile (10 ml) was added DBU at roomtemperature. After stirring for 10 min.,5-(benzyloxy)-1-methyl-1H-indole-2-carbaldehyde (500 mg, 1.88 mmol) wasadded and the mixture was stirred overnight at room temperature. Theresulting mixture was filtered and washed with acetonitrile. Thefiltrate was concentrated in vacuo and then the residue was purified bysilica gel (70 g) chromatography eluted with chloroform to give5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole (221 mg, 34.5%).

[0227] IR (KBr, cm⁻¹): 3050, 2860, 1612, 1456, 1238, 1029

[0228] NMR (CDCl₃, δ): 3.79 (3H, s), 5.11 (2H, s), 6.85-7.60 (16H, m)

[0229] MS: 340 (M+H)⁺

[0230] Preparation 3

[0231] To a solution of5-(benzyloxy)-1-methyl-2-(2-phenylethenyl)-1H-indole (204 mg, 0.601mmol) in EtOH (5 ml) and THF (5 ml) was added 10% palladium on carbon(50 mg). The resulting mixture was stirred under hydrogen (2 atm) for 15h at room temperature. The mixture was filtered through Celite andwashed with EtOH. The filtrate was concentrated in vacuo and then theresidue was purified by silica gel (4.5 g) chromatography eluted withchloroform to give 1-methyl-2-(2-phenylethyl)-1H-indol-5-ol (110 mg,72.8%).

[0232] NMR (CDCl₃, δ): 3.02 (4H, s), 3.57 (3H, s), 4.42 (1H, s) 6.19(1H, s), 6.73 (1H, dd, J=9.2 Hz), 6.96 (1H, d, J=2 Hz), 7.11 (1H, d, J=9Hz), 7.15-7.40 (5H, m)

[0233] MS: 252 (M+H)⁺

EXAMPLE 25

[0234] This compound was prepared by a similar procedure to that ofExample 15.

[0235]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide(25).

[0236] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.02 (4H, s), 3.56 (3H, s),3.57-4.40 (4H, m), 5.33 (1H, brs), 6.20 (1H, s), 6.73 (1H, dd, J=9.2Hz), 6.91 (1H, d, J=2 Hz), 6.94 (1H, brs), 7.11 (1H, d, J=9 Hz),7.15-7.35 (5H, m), 7.44 (1H, s), 7.64 (1H, s)

[0237] MS: 561 (M+H)⁺

EXAMPLE 26

[0238] This compound was prepared by a similar procedure to that ofExample 16.

[0239]1-{(2S,3R)-2-hydroxy-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide(26).

[0240] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.05-2.65 (2H, m), 2.98(4H, s), 3.45-4.35 (7H, m), 5.17 (1H, d, J=5 Hz), 6.12 (1H, s), 6.65(1H, dd, J=9.2 Hz), 6.86 (1H, d, J=2 Hz), 7.03 (1H, brs), 7.10-7.35 (7H,m), 7.69 (1H, s), 7.74 (1H, s)

[0241] MS: 447 (M+H)⁺

EXAMPLE 27

[0242] This compound was prepared by a similar procedure to that ofExample 15.

[0243]1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(27).

[0244] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.90 (9H, s) 1.11(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (4H, m), 5.35 (1H, brs),6.87 (2H, d, J=7 Hz), 6.90 (1H, brs), 7.25-7.60 (8H, m), 7.64 (1H, s)

[0245] MS: 480 (M+H)⁺

EXAMPLE 28

[0246] This compound was prepared by a similar procedure to that ofExample 16.

[0247]1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(28).

[0248] mp. 191-193° C.

[0249] IR (KBr, cm⁻¹): 3600-2800, 1655, 1602, 1485, 1243, 1124, 1084,1038

[0250] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.50-4.30 (4H, m), 5.19 (1H, d, J=5 Hz), 6.85-7.10 (3H, m), 7.15-7.65(8H, m), 7.70 (1H, s), 7.75 (1H, s)

[0251] MS: 366 (M+H)⁺

EXAMPLE 29

[0252] This compound was prepared by a similar procedure to that ofExample 15.

[0253]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-tert-butylphenoxy)-3-pentyl]imidazole-4-carboxamide.

[0254] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10(3H, d, J=6 Hz), 1.28 (9H, s), 2.00-2.60 (2H, m), 3.55-4.35 (4H, m),5.36 (1H, brs), 6.50-7.25 (5H, m), 7.43 (1H, s), 7.63 (1H, s)

[0255] MS: 460 (M+H)⁺

EXAMPLE 30

[0256] This compound was prepared by a similar procedure to that ofExample 16.

[0257]1-[(2S,3R)-5-(3-tert-butylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(30).

[0258] IR (KBr, cm⁻¹): 3600-2800, 1662, 1608, 1572, 1485, 1427, 1271,1238, 1128, 1093

[0259] NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.05-2.60 (2H, m),3.50-4.30 (4H, m), 5.17 (1H, d, J=5 Hz), 6.55-7.35 (6H, m), 7.69 (1H,s), 7.74 (1H, s)

[0260] MS: 346 (M+H)⁺

EXAMPLE 31

[0261] This compound was prepared by a similar procedure to that ofExample 15.

[0262]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(31).

[0263] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (4H, m), 5.36 (1H, brs),6.65-7.35 (8H, m), 7.43 (1H, s), 7.64 (1H, s)

[0264] MS: 486 (M+H)⁺

EXAMPLE 32

[0265] This compound was prepared by a similar procedure to that ofExample 16.

[0266]1-{(2S,3R)-2-hydroxy-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(32).

[0267] IR (KBr, cm⁻¹): 3600-2800, 1657, 1595, 1483, 1419, 1265, 1232,1090, 1057

[0268] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.55-4.35 (4H, m), 5.18 (1H, d, J=5. Hz), 6.70-7.60 (9H, m), 7.71 (1H,s), 7.76 (1H, s)

[0269] MS: 372 (M+H)⁺

EXAMPLE 33

[0270] This compound was prepared by a similar procedure to that ofExample 15.

[0271]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(33).

[0272] NMR (CDCl₃, δ): 0.00 (3H, s), 0.05 (3H, s), 0.91 (9H, s), 1.08(3H, d, J=6 Hz), 2.00-2.75 (2H, m), 3.55-4.45 (4H, m), 5.31 (1H, brs),6.75-7.45 (8H, m), 7.55-7.70 (2H, m)

[0273] MS: 486 (M+H)⁺

EXAMPLE 34

[0274] This compound was prepared by a similar procedure to that ofExample 16.

[0275]1-{(2S,3R)-2-hydroxy-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(34).

[0276] IR (KBr, cm⁻¹): 3600-2800, 1658, 1592, 1483, 1446, 1415, 1238,1119, 1090, 1057

[0277] NMR (DMSO-d₆, δ): 0.96 (3H, d, J=6 Hz), 2.10-2.70 (2H, m),3.60-4.40 (4H, m), 5.21 (1H, d, J=5 Hz), 6.90-7.35 (6H, m), 7.50-7.80(5H, m)

[0278] MS: 372 (M+H)⁺

[0279] Preparation 4

[0280] To a stirred solution of 2-benzyl-4-(3-methoxyphenyl)thiazole(1.0 g, 3.55 mmol) in CH₂Cl₂ (20 ml) was added a solution of 1.0 M BBr₃in CH₂Cl₂ (4.26 ml) at −78° C. The resulting mixture was stirred at −78°C. for 30 min and then allowed to warm up to room temperature. Themixture was quenched with water and extracted with ether. The organiclayer was washed with brine, dried (magnesium sulfate) and evaporated invacuo. The residue was triturated with chloroform and dried underreduced pressure to give 3-(2-benzylthiazol-4-yl)phenol (760 mg, 80%).

[0281] IR (KBr, cm⁻¹): 3600-2600, 1599, 1498, 1440, 1246, 1176, 1144,1070

[0282] NMR (DMSO-d₆, δ): 4.38 (2H, s), 6.65-6.80 (1H, m), 7.10-7.45 (8H,m), 7.86 (1H, s), 9.47 (1H, brs)

[0283] MS: 268 (M+H)⁺

EXAMPLE 35

[0284] This compound was prepared by a similar procedure to that ofExample 15.

[0285]1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide(35).

[0286] NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.05-2.65 (2H, m), 3.60-4.45 (6H, m), 5.32 (1H, brs),6.70-7.80 (1H, m), 6.92 (1H, brs), 7.20-7.50 (10H, m), 7.65 (1H, s)

[0287] MS: 577 (M+H)⁺

EXAMPLE 36

[0288] This compound was prepared by a similar procedure to that ofExample 16.

[0289]1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(36).

[0290] IR (KBr, cm⁻¹): 3600-2800, 1658, 1592, 1495, 1460, 1415, 1240,1119, 1090, 1059

[0291] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.50-4.30 (4H, m), 4.38 (2H, s), 5.18 (1H, d, J=5 Hz), 6.70-7.55 (11H,m), 7.71 (1H, s), 7.76 (1H, s), 7.96 (1H, s)

[0292] MS: 463 (M+H)⁺

EXAMPLE 37

[0293] This compound was prepared by a similar procedure to that ofExample 15.

[0294]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-phenylthiazol-4-yl)phenoxy]-3-pentyl}imidazole-4-carboxamide(37).

[0295] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.60-4.40 (4H, m), 5.34 (1H, brs),6.70-7.00 (2H, m), 7.20-7.75 (9H, m), 7.95-8.10 (2H, m)

[0296] MS: 563 (M+H)⁺

EXAMPLE 38

[0297] This compound was prepared by a similar procedure to that ofExample 16.

[0298]1-{(2S,3R)-2-hydroxy-5-[3-(2-phenylthiazol-4-yl)phenoxy]-3-pentyl}imidazole-4-carboxamide(38).

[0299] IR (KBr, cm¹⁻): 3600-2800, 1658, 1593, 1479, 1240, 1169, 1090,1059

[0300] NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10-2.65 (2H, m),3.55-4.35 (4H, m), 5.20 (1H, d, J=5 Hz), 6.75-6.95 (1H, m), 7.03 (1H,brs), 7.25 (1H, brs), 7.35 (1H, t, J=8 Hz), 7.40-7.69 (5H, m), 7.72 (1H,s), 7.77 (1H, s), 7.95-8.10 (2H, m), 8.19 (1H, s)

[0301] MS: 449 (M+H)⁺

EXAMPLE 39

[0302] This compound was prepared by a similar procedure to that ofExample 15.

[0303]1-[(2S,3R)-5-(3-bromophenoxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(39).

[0304] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.09(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.50-4.30 (4H, m), 5.36 (1H, brs),6.60-7.15 (5H, m), 7.41 (1H, s), 7.62 (1H, s)

[0305] MS: 482 (M+H)⁺ (⁷⁹Br), 484 (M+H)⁺ (⁸¹Br)

EXAMPLE 40

[0306] This compound was prepared by a similar procedure to that ofExample 16.

[0307]1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(40).

[0308] IR (KBr, cm⁻¹): 3600-2800, 1664, 1593, 1236, 1092

[0309] NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.05-2.60 (2H, m),3.50-4.30 (4H, m), 5.18 (1H, d, J=5 Hz), 6.80-7.35 (6H, m), 7.69 (1H,s), 7.74 (1H, s)

[0310] MS: 368 (M+H)⁺ (⁷⁹Br), 370 (M+H)⁺ (⁸¹Br)

EXAMPLE 41

[0311] To a solution of1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamidein DME (5 ml) was added Pd(PPh₃)₄ (29.3 mg, 0.025 mmol)at ambienttemperature under N₂. After stirring for 20 min.,benzothiophene-2-boronic acid (54.2 mg, 0.304 mmol) and a solution ofNa₂CO₃ (40.3 mg, 0.38 mmol) in H₂O (1 ml) were added and the mixture wasrefluxed for 3 h. The mixture was cooled to room temperature andpartitioned between ethyl acetate (20 ml) and H₂O. The organic layer waswashed successively with saturated NaHCO₃ aqueous solution, H₂O and thenbrine, dried (sodium sulfate) and evaporated in vacuo. The residue waspurified by silica gel chromatography eluting with chloroform/methanol(100:1 to 20:1) to give1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(41) (66.9 mg, 62.6%).

[0312] IR (KBr, cm⁻¹): 3600-2800, 1658, 1594, 1432, 1261, 1171, 1092

[0313] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.50-4.35 (4H, m), 5.20 (1H, d, J=5 Hz), 6.80-7.50 (8H, m), 7.65-8.05(5H, m)

[0314] MS: 422 (M+H)⁺

EXAMPLE 42

[0315] This compound was prepared by a similar procedure to that ofExample 15.

[0316]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(42).

[0317] IR (KBr, cm⁻¹): 3600-2800, 1666, 1600, 1259, 1191, 1118

[0318] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.09(3H, d, J=6 Hz), 2.00-2.60 (2H, m), 3.13 (4H, t, J=5 Hz), 3.50-4.30 (8H,m), 5.34 (1H, brs), 6.20-6.65 (3H, m), 6.92 (1H, brs), 7.13 (1H, t, J=8Hz), 7.41 (1H, s), 7.62 (1H, s)

[0319] MS: 489 (M+H)⁺

EXAMPLE 43

[0320] This compound was prepared by a similar procedure to that ofExample 16.

[0321]1-{(2S,3R)-2-hydroxy-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(43).

[0322] IR (KBr, cm⁻¹): 3600-2800, 1660, 1600, 1493, 1450, 1261, 1190,1117

[0323] NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.05-2.55 (2H, m), 3.04(4H, t, J=5 Hz), 3.55-4.30 (8H, m), 5.16 (1H, brs), 6.20-6.65 (3H, m),6.90-7.15 (2H, m), 7.24 (1H, brs), 7.68 (1H, s), 7.72 (1H, s)

[0324] MS: 375 (M+H)⁺

[0325] Preparation 5

[0326] To a solution of 3-iodophenol (1.0 g, 4.55 mmol) in DME (10 ml)was added Pd(PPh₃)₄ (263 mg, 0.227 mmol) at ambient temperature underN₂. After stirring for 20 min., 5-chlorothiophene-2-boronic acid (886mg, 5.45 mmol) and a solution of Na₂CO₃ (723 mg, 6.82 mmol) in H₂O (3ml) were added and the mixture was refluxed for 2 h. The mixture wascooled to room temperature and partitioned between ethyl acetate (30 ml)and H₂O. The organic layer was washed with saturated NaHCO₃ aqueoussolution, H₂O and then brine, dried (sodium sulfate) and evaporated invacuo. The residue was purified by silica gel (15 g) chromatographyeluting with hexane/ethyl acetate (10:1) to give3-(5-chloro-2-thienyl)phenol (0.88 g, 91.9%).

[0327] IR (KBr, cm⁻¹) : 3600-2800, 1599, 1454, 1250, 1217, 1088, 787

[0328] NMR (CDCl₃, δ): 4.87 (1H, s), 6.70-6.80 (1H, m), 6.88 (1H, d, J=4Hz), 6.98 (1H, t, J=2 Hz), 7.00-7.32 (3H, m)

[0329] MS: 209 (M−H)⁻ (³⁵Cl), 211 (M−H)⁻ (³⁷Cl)

EXAMPLE 44

[0330] This compound was prepared by a similar procedure to that ofExample 15.

[0331]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-chloro-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(44).

[0332] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.05-2.65 (2H, m), 3.55-4.33 (4H, m), 5.32 (1H, brs),6.65-7.35 (7H, m), 7.43 (1H, s), 7.64 (1H, s)

[0333] MS: 520 (M+H)⁺ (³⁵Cl), 522 (M+H)⁺ (³⁷Cl)

EXAMPLE 45

[0334] This compound was prepared by a similar procedure to that ofExample 16.

[0335]1-{(2S,3R)-5-[3-(5-chloro-2-thienyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(45).

[0336] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1485, 1425, 1265, 1088

[0337] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.65 (2H, m),3.50-4.30 (4H, m), 5.18 (1H, d, J=5 Hz), 6.70-7.45 (8H, m), 7.70 (1H,s), 7.75 (1H, s)

[0338] MS: 406 (M+H)⁺ (³⁵Cl), 408 (M+H)⁺ (³⁷Cl)

[0339] Preparation 6

[0340] This compound was prepared by a similar procedure to that ofPreparation 5.

[0341] 3-(5-Methyl-2-thienyl)phenol.

[0342] IR (KBr, cm⁻¹): 3600-2800, 1585, 1444, 1223, 1186, 847, 779

[0343] NMR (CDCl₃, δ): 2.50 (3H, s), 4.81 (1H, s), 6.60-6.80 (2H, m),6.95-7.30 (4H, m)

[0344] MS: 189 (M−H)⁻

EXAMPLE 46

[0345] This compound was prepared by a similar procedure to that ofExample 15.

[0346]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(46).

[0347] NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.10(3H, d, J=6 Hz), 2.00-2.65 (5H, m), 3.55-4.35 (4H, m), 5.34 (1H, brs),6.60-7.30 (7H, m), 7.43 (1H, s), 7.64 (1H, s)

[0348] MS: 500 (M+H)⁺

EXAMPLE 47

[0349] This compound was prepared by a similar procedure to that ofExample 16.

[0350]1-{(2S,3R)-2-hydroxy-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(47).

[0351] IR (KBr, cm⁻¹): 3600-2800, 1658, 1599, 1495, 1427, 1267, 1228,1090, 1053

[0352] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (5H, m),3.50-4.30 (4H, m), 5.18 (1H, d, J=5 Hz), 6.65-7.35 (8H, m), 7.70 (1H,s), 7.75 (1H, s)

[0353] MS: 386 (M+H)⁺

EXAMPLE 48

[0354] This compound was prepared by a similar procedure to that ofExample 15.

[0355]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(48).

[0356] NMR (CDCl₃, δ): 0.01 (3H, s), 0.06 (3H, s), 0.88 (9H, s), 1.07(3H, d, J=6 Hz), 2.10-2.70 (2H, m), 3.90-4.65 (4H, m), 5.46 (1H, brs),6.83 (1H, d, J=9 Hz), 6.95 (1H, brs), 7.10-7.85 (6H, m), 7.98 (1H, d,J=9 Hz)

[0357] MS: 455 (M+H)⁺

EXAMPLE 49

[0358] This compound was prepared by a similar procedure to that ofExample 16.

[0359]1-[(2S,3R)-2-hydroxy-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide(49).

[0360] IR (KBr, cm⁻¹): 3600-2800, 1658, 1608, 1425, 1267, 1238, 1111,1088

[0361] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.20-2.45 (2H, m),3.75-4.45 (4H, m), 5.17 (1H, d, J=5 Hz), 6.95 (1H, d, J=9 Hz), 7.05 (1H,brs), 7.25 (1H, brs), 7.35-7.95 (6H, m), 8.21 (1H, d, J=9 Hz)

[0362] MS: 341 (M+H)⁺

EXAMPLE 50

[0363] This compound was prepared by a similar procedure to that ofExample 15.

[0364]1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide(50).

[0365] IR (KBr, cm⁻¹): 3600-2800, 1666, 1558, 1454, 1242, 1103, 1038

[0366] NMR (CDCl₃, δ): 0.04 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.65-4.35 (4H, m), 5.33 (1H, brs),6.80-7.05 (2H, m), 7.30-7.70 (4H, m), 7.52-7.90 (5H, m)

[0367] MS: 521 (M+H)⁺

EXAMPLE 51

[0368] This compound was prepared by a similar procedure to that ofExample 16.

[0369]1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(51).

[0370] IR (KBr, cm⁻¹): 3600-2800, 1658, 1592, 1554, 1450, 1236, 1088

[0371] NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.55-4.35 (4H, m), 5.20 (1H, d, J=5 Hz), 7.02 (1H, brs), 7.09-7.19 (1H,m), 7.24 (1H, brs), 7.33-7.90 (9H, m)

[0372] MS: 407 (M+H)⁺

EXAMPLE 52

[0373] This compound was prepared by a similar procedure to that ofExample 15.

[0374]1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide(52).

[0375] NMR (CDCl₃, δ): 0.04 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.60-4.35 (4H, m), 5.36 (1H, brs),6.70-6.85 (1H, m), 6.92 (1H, brs), 7.01 (1H, s), 7.15-7.70 (10H, m)

[0376] MS: 520 (M+H)⁺

EXAMPLE 53

[0377] This compound was prepared by a similar procedure to that ofExample 16.

[0378]1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-hydroxy-3-pentyl)imidazole-4-carboxamide(53).

[0379] IR (KBr, cm⁻¹): 3600-2800, 1658, 1599, 1568, 1450, 1261, 1234,1090, 1055

[0380] NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.60-4.35 (4H, m), 5.19 (1H, d, J=5 Hz), 6.80-6.95 (1H, m), 7.02 (1H,brs), 7.15-7.53 (7H, m), 7.56-7.85 (4H, m)

[0381] MS: 406 (M+H)⁺

EXAMPLE 54

[0382] This compound was prepared by a similar procedure to that ofExample 15.

[0383]1-{2S,3R}-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide(54).

[0384] MS: 520 (M+H)⁺

EXAMPLE 55

[0385] This compound was prepared by a similar procedure to that ofExample 16.

[0386]1-{(2S,3R)-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(55).

[0387] IR (KBr, cm⁻¹): 3600-2800, 1658, 1599, 1460, 1267, 1236, 1095

[0388] NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.60-4.35 (4H, m), 5.21 (1H, d, J=5 Hz), 6.90-7.30 (5H, m), 7.42 (1H, t,J=8 Hz), 7.50-7.85 (6H, m)

[0389] MS: 406 (M+H)⁺

[0390] Preparation 7

[0391] This compound was prepared by a similar procedure to that ofPreparation 5.

[0392] 4′-Chloro-1,1′-biphenyl-3-ol.

[0393] IR (KBr, cm⁻¹): 3600-2800, 1593, 1475, 1292, 1201, 1083, 825, 777

[0394] NMR (CDCl₃, δ): 4.93 (1H, s), 6.75-6.90 (1H, m), 7.02 (1H, t, J=2Hz), 7.05-7.60 (6H, m)

[0395] MS: 203 (M−H)³¹ (³⁵Cl), 205 (M−H)⁻ (³⁷Cl)

EXAMPLE 56

[0396] This compound was prepared by a similar procedure to that ofExample 15.

[0397]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(56).

[0398] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (4H, m), 5.34 (1H, brs),6.65-7.18 (4H, m), 7.20-7.55 (6H, m), 7.64 (1H, s)

[0399] MS: 514 (M+H)⁺ (³⁵Cl), 516 (M+H)⁺ (³⁷Cl)

EXAMPLE 57

[0400] This compound was prepared by a similar procedure to that ofExample 16.

[0401]1-{(2S,3R)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(57).

[0402] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1473, 1263, 1238, 1091,1060

[0403] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.55-4.30 (4H, m), 5.17 (1H, d, J=5 Hz), 6.75-7.55 (8H, m), 7.60-7.85(4H, m)

[0404] MS: 400 (M+H)⁺ (³⁵Cl), 402 (M+H)⁺ (³⁷Cl)

[0405] Preparation 8

[0406] This compound was prepared by a similar procedure to that ofPreparation 5.

[0407] 3′-Chloro-1,1′-biphenyl-3-ol.

[0408] IR (KBr, cm⁻¹): 3600-2800, 1595, 1466, 1238, 1199, 1092, 1045,773

[0409] NMR (CDCl₃, δ): 4.91 (1H, s), 6.75-6.90 (1H, m), 7.03 (1H, t, J=2Hz), 7.08-7.60 (6H, m)

[0410] MS: 203 (M−H)⁻ (³⁵Cl), 205 (M−H)⁻ (³⁷Cl)

EXAMPLE 58

[0411] This compound was prepared by a similar procedure to that ofExample 15.

[0412]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(58).

[0413] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s) 1.11(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (4H, m), 5.33 (1H, brs),6.70-7.18 (4H, m), 7.20-7.45 (5H, m), 7.53 (1H, s), 7.64 (1H, s)

[0414] MS: 514 (M+H)⁺ (³⁵Cl), 516 (M+H)⁺ (³⁷Cl)

EXAMPLE 59

[0415] This compound was prepared by a similar procedure to that ofExample 16.

[0416]1-{(2S,3R)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(59).

[0417] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1465, 1263, 1205, 1090,1085, 1045

[0418] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.55-4.30 (4H, m), 5.18 (1H, d, J=5 Hz), 6.80-7.80 (12H, m)

[0419] MS: 400 (M+H)⁺ (³⁵Cl), 402 (M+H)⁺ (³⁷Cl)

[0420] Preparation 9

[0421] This compound was prepared by a similar procedure to that ofPreparation 5.

[0422] 2′-Chloro-1,1′-biphenyl-3-ol.

[0423] IR (KBr, cm⁻¹) 3600-2800, 1589, 1462, 1240, 1190, 1078, 1039

[0424] NMR (CDCl₃, δ): 4.90 (1H, s), 6.75-7.05 (3H, m), 7.15-7.52 (5H,m)

[0425] MS: 203 (M−H)⁻ (³⁵Cl), 205 (M−H)⁻ (³⁷Cl)

EXAMPLE 60

[0426] This compound was prepared by a similar procedure to that ofExample 15.

[0427]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(60).

[0428] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.10(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (4H, m), 5.33 (1H, brs),6.75-7.05 (4H, m), 7.20-7.50 (6H, m), 7.63 (1H, s)

[0429] MS: 514 (M+H)⁺ (³⁵Cl), 516 (M+H)⁺ (³⁷Cl)

EXAMPLE 61

[0430] This compound was prepared by a similar procedure to that ofExample 16.

[0431]1-{(2S,3R)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(61).

[0432] IR (KBr, cm⁻¹): 3600-2800, 1658, 1589, 1464, 1259, 1203, 1124,1085, 1045

[0433] NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.55-4.30 (4H, m), 5.1.6 (1H, d, J=5 Hz), 6.80-7.05 (4H, m), 7.23 (1H,brs), 7.28-7.60 (5H, m), 7.69 (1H, s), 7.74 (1H, s)

[0434] MS: 400 (M+H)⁺ (³⁵Cl), 402 (M+H) ⁺ (³⁷Cl)

EXAMPLE 62

[0435] This compound was prepared by a similar procedure to that ofExample 15.

[0436]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(62).

[0437] IR (KBr, cm⁻¹): 3600-2800, 1666, 1602, 1251, 1103, 1034

[0438] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (7H, m), 5.32 (1H, brs),6.65-7.55 (10H, m), 7.64 (1H, s)

[0439] MS: 510 (M+H)⁺

EXAMPLE 63

[0440] This compound was prepared by a similar procedure to that ofExample 16.

[0441]1-{(2S,3R)-2-hydroxy-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(63).

[0442] IR (KBr, cm⁻): 3600-2800, 1660, 1601, 1479, 1410, 1248, 1205,1184, 1024

[0443] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.55-4.30 (7H, m), 5.17 (1H, d, J=5 Hz), 6.70-7.35 (8H, m), 7.57 (2H, d,J=9 Hz), 7.70 (1H, s), 7.75 (1H, s)

[0444] MS: 396 (M+H)⁺

[0445] Preparation 10

[0446] This compound was prepared by a similar procedure to that ofPreparation 5.

[0447] 3′-Methoxy-1,1′-biphenyl-3-ol.

[0448] IR (KBr, cm⁻¹: 3600-2800, 1599, 1238, 1161, 1088, 802

[0449] NMR (CDCl₃, δ): 3.86 (3H, s), 4.88 (1H, s), 6.75-6.95 (2H, m),7.00-7.40 (6H, m)

[0450] MS: 199 (M−H)⁻

EXAMPLE 64

[0451] This compound was prepared by a similar procedure to that ofExample 15.

[0452]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(64).

[0453] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.10(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.60-4.35 (7H, m), 5.32 (1H, brs),6.70-7.40 (9H, m), 7.43 (1H, s), 7.64 (1H, s)

[0454] MS: 510 (M+H)⁺

EXAMPLE 65

[0455] This compound was prepared by a similar procedure to that ofExample 16.

[0456]1-{(2S,3R)-2-hydroxy-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(65).

[0457] IR (KBr, cm⁻¹): 3600-2800, 1660, 1599, 1473, 1234, 1090

[0458] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.55-4.30 (7H, m), 5.19 (1H, d, J=5 Hz), 6.80-7.45 (10H, m), 7.71 (1H,s), 7.75 (1H, S)

[0459] MS: 396 (M+H)⁺

[0460] Preparation 11

[0461] This compound was prepared by a similar procedure to that ofPreparation 5.

[0462] 3-(2-Methoxy-5-pyridyl)phenol.

[0463] IR (KBr, cm⁻¹): 3600-2800, 1603, 1240, 1130, 1088, 1038, 791

[0464] NMR (CDCl₃, δ): 3.99 (3H, s), 5.41 (1H, s), 6.75-6.90 (2H, m),7.01 (1H, t, J=2 Hz), 7.04-7.15 (1H, m), 7.31 (1H, t, J=8 Hz), 7.78 (1H,dd, J=8.2 Hz), 8.39 (1H, d, J=2 Hz)

[0465] MS: 202 (M+H)⁺

EXAMPLE 66

[0466] This compound was prepared by a similar procedure to that ofExample 15.

[0467]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-methoxy-5-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(66).

[0468] IR (KBr, cm⁻¹): 3600-2800, 1666, 1602, 1284, 1257, 1099, 1027

[0469] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.55-4.35 (7H, m), 5.33 (1H, brs),6.70-7.40 (6H, m), 7.43 (1H, s), 7.64 (1H, s), 7.75 (1H, dd, J=8,3 Hz),8.35 (1H, d, J=3 Hz)

[0470] MS: 511 (M+H)⁺

EXAMPLE 67

[0471] This compound was prepared by a similar procedure to that ofExample 16.

[0472]1-{(2S,3R)-2-hydroxy-5-[3-(2-methoxy-5-pyridyl)phenoxyl-3-pentyl}imidazole-4-carboxamide(67).

[0473] IR (KBr, cm⁻¹): 3600-2800, 1660, 1602, 1479, 1282, 1242, 1092,1024

[0474] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.55-4.30 (7H, m), 5.19 (1H, d, J=5 Hz), 6.75-7.40 (7H, m), 7.71 (1H,s), 7.75 (1H, s), 7.99 (1H, dd, J=9.3 Hz), 8.46 (1H, d, J=3 Hz)

[0475] MS: 397 (M+H)⁺

EXAMPLE 68

[0476] This compound was prepared by a similar procedure to that ofExample 15.

[0477]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide(68).

[0478] NMR (CDCl₃, δ): 0.00 (3H, s), 0.04 (3H, s), 0.88 (9H, s) 1.07(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.90-4.60 (4H, m), 5.33 (1H, brs),6.62 (1H, d, J=8 Hz), 6.91 (1H, brs), 7.25-7.50 (5H, m), 7.60 (1H, d,J=8 Hz), 7.65 (1H, s), 7.88-8.00 (2H, m)

[0479] MS: 481 (M+H)⁺

EXAMPLE 69

[0480] This compound was prepared by a similar procedure to that ofExample 16.

[0481]1-{(2S,3R)-2-hydroxy-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide(69).

[0482] IR (KBr, cm⁻¹): 3600-2800, 1658, 1581, 1444, 1248, 1088

[0483] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.75-4.45 (4H, m), 5.17 (1H, d, J=5 Hz), 6.71 (1H, d, J=8 Hz), 7.03 (1H,brs), 7.24 (1H, brs), 7.32-7.60 (4H, m), 7.60 (1H, d, J=8 Hz), 7.65-8.10(5H, m)

[0484] MS: 367 (M+H)⁺

EXAMPLE 70

[0485] This compound was prepared by a similar procedure to that ofExample 15.

[0486]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(70).

[0487] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.00-2.65 (2H, m), 3.60-4.35 (4H, m), 5.33 (1H, brs),6.70-7.20 (6H, m), 7.24-7.56 (4H, m), 7.64 (1H, s)

[0488] MS: 498 (M+H)⁺

EXAMPLE 71

[0489] This compound was prepared by a similar procedure to that ofExample 16.

[0490]1-{(2S,3R)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(71).

[0491] IR (KBr, cm⁻¹) : 3600-2800, 1658, 1600, 1481, 1234, 1092

[0492] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.55-4.30 (4H, m), 5.18 (1H, d, J=5 Hz), 6.75-7.40 (8H, m), 7.55-7.85(4H, m)

[0493] MS: 384 (M+H)⁺

[0494] Preparation 12

[0495] This compound was prepared by a similar procedure to that ofPreparation 5.

[0496] 4′-trifluoromethyl-1,1′-biphenyl-3-ol.

[0497] IR (KBr, cm⁻¹): 3600-2800, 1589, 1458, 1408, 1325, 1190, 1134,1070, 839, 781

[0498] NMR (CDCl₃, δ): 4.90 (1H, s), 6.80-6.95 (1H, m), 7.07 (1H, t, J=2Hz), 7.10-7.22 (1H, m), 7.34 (1H, t, J=8 Hz), 7.60-7.75 (4H, m)

[0499] MS: 237 (M−H)⁻

EXAMPLE 72

[0500] This compound was prepared by a similar procedure to that ofExample 15.

[0501]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl)oxy}-3-pentyl]imidazole-4-carboxamide(72).

[0502] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s) 1.11(3H, d, J=6 Hz), 2.10-2.60 (2H, m), 3.65-4.30 (4H, m), 5.33 (1H, brs),6.82 (1H, m), 6.91 (1H, brs), 7.00 (1H, t, J=2 Hz), 7.17 (1H, m), 7.34(1H, t, J=8 Hz), 7.43 (1H, s), 7.62-7.72 (5H, m)

[0503] MS: 548 (M+H)⁺

EXAMPLE 73

[0504] This compound was prepared by a similar procedure to that ofExample 16.

[0505]1-[(2S,3R)-2-hydroxy-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]oxy}-3-pentyl]imidazole-4-carboxamide(73).

[0506] IR (KBr, cm⁻¹): 3600-2800, 1658, 1599, 1328, 1165, 1119, 1070

[0507] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.60-4.35 (4H, m), 5.18 (1H, d, J=5 Hz), 6.85-7.45 (6H, m), 7.63-8.00(6H, m)

[0508] MS: 434 (M+H)⁺

[0509] Preparation 13

[0510] This compound was prepared by a similar procedure to that ofExample 15.

[0511] Ethyl1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxylate.

[0512] NMR (CDCl₃, δ): −0.04 (3H, s), 0.03 (3H, s), 0.91 (9H, s), 1.08(3H, d, J=6 Hz), 1.34 (3H, t, J=7 Hz), 2.00-2.65 (2H, m), 3.40-4.40 (6H,m), 6.38 (2H, t, J=2 Hz) 7.06 (2H, t, J=2 Hz), 7.13 (2H, s), 7.30-7.55(3H, m), 7.65-7.80 (3H, m)

[0513] MS: 548 (M+H)⁺

[0514] Preparation 14

[0515] This compound was prepared by a similar procedure to that ofExample 16.

[0516] Ethyl1-{(2S,3R)-2-hydroxy-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxylate.

[0517] IR (KBr, cm⁻¹): 3600-2800, 1714, 1506, 1236, 1192, 1099

[0518] NMR (CDCl₃, δ): 1.14 (3H, d, J=6 Hz), 1.34 (3H, t, J=7 Hz),2.05-2.65 (2H, m), 2.81 (1H, br), 3.40-4.40 (6H, m), 6.39 (2H, t, J=2Hz), 7.07 (2H, t, J=2 Hz), 7.16 (2H, s), 7.30-7.60 (3H, m), 7.65-7.85(3H, m)

[0519] MS: 434 (M+H)⁺

EXAMPLE 74

[0520] This compound was prepared by a similar procedure to that ofPreparation 1.

[0521]1-{(2S,3R)-2-hydroxy-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxamide(74).

[0522] IR (KBr, cm⁻¹): 3600-2800, 1658, 1595, 1500, 1463, 1410, 1255,1097

[0523] NMR (DMSO-d₆, δ): 0.92 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.50-4.25 (4H, m), 5.18 (1H, d, J=5 Hz), 6.29 (2H, t, J=2 Hz), 7.02 (1H,brs), 7.20 (2H, t, J=2 Hz), 7.24 (1H, brs), 7.35-7.55 (4H, m), 7.72 (1H,s), 7.75-7.95 (3H, m)

[0524] MS: 405 (M+H)⁺

[0525] Preparation 15

[0526] This compound was prepared by a similar procedure to that ofPreparation 13.

[0527] Ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(1-methyl-1H-indol-5-yloxy)-3-pentyl]imidazole-4-carboxylate.

[0528] NMR (CDCl₃, δ): 0.01 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.13(3H, d, J=6 Hz), 1.37 (3H, t, J=7 Hz), 2.00-2.60 (2H, m), 3.55-4.45 (9H,m), 6.35 (1H, d, J=3 Hz), 6.78 (1H, dd, J=9.2 Hz), 6.97 (1H, d, J=2 Hz),7.01 (1H, d, J=3 Hz), 7.18 (1H, d, J=9 Hz), 7.52 (1H, s), 7.68 (1H, s)

[0529] MS: 486 (M+H)⁺

[0530] Preparation 16

[0531] This compound was prepared by a similar procedure to that ofExample 16.

[0532] Ethyl1-[(2S,3R)-2-hydroxy-5-(1-methyl-1H-indol-5-yloxy)-3-pentyl]imidazole-4-carboxylate.

[0533] IR (KBr, cm⁻¹): 3600-2800, 1699, 1313, 1234, 1147, 1026

[0534] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz),2.10-2.55 (2H, m), 3.45-4.35 (9H, m), 5.18 (1H, d, J=5 Hz), 6.26 (1H, d,J=3 Hz), 6.72 (1H, dd, J=9.2 Hz), 6.94 (1H, d, J=2 Hz), 7.23 (1H, d, J=3Hz), 7.28 (1H, d, J=9 Hz), 7.77 (1H, s), 7.96 (1H, s)

[0535] MS: 372 (M+H)⁺

EXAMPLE 75

[0536] This compound was prepared by a similar procedure to that ofPreparation 1.

[0537]1-[(2S,3R)-2-hydroxy-5-(1-methyl-1H-indol-5-yloxy)-3-pentyl]imidazole-4-carboxamide(75).

[0538] mp. 211-213.5° C.

[0539] IR (KBr, cm⁻¹): 3600-2800, 1666, 1583, 1495, 1398, 1242, 1151,1103

[0540] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.05-2.55 (2H, m)3.45-4.35 (7H, m), 5.18 (1H, brs), 6.27 (1H, d, J=3 Hz), 6.73 (1H, dd,J=9.2 Hz), 6.94 (1H, d, J=2 Hz), 7.01 (1H, brs), 7.15-7.35 (3H, m), 7.69(1H, s), 7.74 (1H, s)

[0541] MS: 343 (M+H)⁺

[0542] Preparation 17

[0543] To a stirred mixture of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate(500 mg, 1.4 mmol) and methanesulfonyl chloride (321 mg, 2.8 mmol) indichloromethane (15 ml) was added dropwise triethylamine (284 mg, 2.8mmol) at ice-bath temperature. After 1 h, the reaction mixture waspartitioned between dichloromethane and water. The organic layer waswashed with brine, dried (magnesium sulfate), and concentrated in vacuoto give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate(642 mg, 105%) as a syrup. This material was used for the next reactionwithout further purification.

[0544] Preparation 18

[0545] To a mixture of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxylate(160 mg, 0.368 mmol) and 2-naphthalenethiol (118 mg, 0.736 mmol) in DMF(5 ml) was added potassium carbonate (102 mg, 0.736 mmol) at roomtemperature and the reaction mixture was stirred for 2 hours. Theresulting reaction mixture was poured into water (25 ml) and extractedwith ethyl acetate. The organic layer was washed with brine, dried(sodium sulfate) and evaporated in vacuo. The residue was purified bysilica gel (10 g) chromatography eluting with chloroform/methanol (100:1to 50:1) to give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxylate(146 mg, 79.5%).

[0546] IR (neat, cm⁻¹): 3425, 2954, 2860, 1722, 1591, 1238, 1089

[0547] NMR (CDCl₃, δ): −0.08 (3H, s), −0.04 (3H, s), 0.78 (9H, s), 1.00(3H, d, J=6 Hz), 1.39 (3H, t, J=7 Hz), 2.00-2.35 (2H, m), 2.65-3.10 (2H,m), 3.75-4.25 (2H, m), 4.37 (2H, q, J=7 Hz), 7.30-7.55 (4H, m), 7.60(1H, s), 7.65-7.85 (4H, m)

[0548] MS: 499 (M+H)⁺

[0549] Preparation 19

[0550] This compound was prepared by a similar procedure to that ofExample 16.

[0551] Ethyl1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxylate.

[0552] IR (neat, cm⁻¹): 3600-2800, 1720, 1226, 1193, 1126

[0553] NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz),2.10-2.35 (2H, m), 2.70-2.95 (2H, m), 3.70-4.30 (4H, m), 5.14 (1H, d,J=5 Hz), 7.30-7.55 (3H, m), 7.62-7.80 (6H, m)

[0554] MS: 385 (M+H)⁺

EXAMPLE 76

[0555] This compound was prepared by a similar procedure to that ofPreparation 1.

[0556]1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxamide(76).

[0557] IR (KBr, cm⁻¹): 3600-2800, 1657, 1591, 1413, 1261, 1240, 1126,1097, 1076

[0558] NMR (DMSO-d₆, δ): 0.87 (3H, d, J=6 Hz), 2.05-2.40 (2H, m)2.65-3.00 (2H, m), 3.70-4.20 (2H, m), 5.13 (1H, d, J=5 Hz), 7.06 (1H,brs), 7.28 (1H, brs), 7.30-7.60 (3H, m), 7.62-7.95 (6H, m)

[0559] MS: 356 (M+H)⁺

[0560] Preparation 20

[0561] This compound was prepared by a similar procedure to that ofPreparation 18.

[0562] Ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxylate.

[0563] IR (neat, cm⁻¹): 3446, 2956, 2858, 1724, 1236, 1184, 1130

[0564] NMR (CDCl₃, δ): −0.09 (3H, s), −0.02 (3H, s), 0.82 (9H, s) 0.96(3H, d, J=6 Hz), 1.39 (3H, t, J=7 Hz), 2.00-2.25 (2H, m), 2.45-3.05 (2H,m), 3.75-4.20 (2H, m), 4.37 (2H, q, J=7 Hz), 7.30-7.62 (6H, m),7.70-7.90 (2H, m), 8.37 (1H, dd, J=9.2 Hz)

[0565] MS: 499 (M+H)⁺

[0566] Preparation 21

[0567] This compound was prepared by a similar procedure to that ofExample 16.

[0568] Ethyl1-[(2S,3R)-2-hydroxy-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxylate.

[0569] IR (neat, cm⁻¹): 3600-2800, 1720, 1223, 1196, 1126

[0570] NMR (DMSO-d₆, δ): 0.85 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz),2.05-2.35 (2H, m), 2.65-2.95 (2H, m), 3.65-4.30 (4H, m), 5.14 (1H, d,J=5 Hz), 7.35-7.66 (4H, m), 7.72-8.03 (4H, m), 8.12-8.28 (1H, m)

[0571] MS: 385 (M+H)⁺

EXAMPLE 77

[0572] This compound was prepared by a similar procedure to that ofPreparation 1.

[0573]1-[(2S,3R)-2-hydroxy-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxamide(77).

[0574] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1413, 1336, 1261, 1128

[0575] NMR (DMSO-d₆, δ): 0.85 (3H, d, J=6 Hz), 2.05-2.35 (2H, m),2.60-2.95 (2H, m), 3.65-4.25 (2H, m), 5.12 (1H, d, J=5 Hz), 7.04 (1H,brs), 7.27 (1H, brs), 7.35-8.03 (8H, m), 8.13-8.28 (1H, m)

[0576] MS: 356 (M+H)⁺

[0577] Preparation 22

[0578] This compound was prepared by a similar procedure to that ofPreparation 18.

[0579] Ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxylate.

[0580] IR (neat, cm⁻¹): 3450, 2954, 2858, 1722, 1238, 1182, 1136, 1091

[0581] NMR (CDCl₃, δ): −0.06 (3H, s), 0.00 (3H, s), 0.79 (9H, s), 1.04(3H, d, J=6 Hz), 1.40 (3H, t, J=7 Hz), 2.20-2.60 (2H, m), 2.80-3.50 (2H,m), 3.85-4.25 (2H, m), 4.38 (2H, q, J=7 Hz), 7.18 (1H, d, J=9 Hz),7.35-7.80 (5H, m), 7.84-8.00 (2H, m)

[0582] MS: 500 (M+H)⁺

[0583] Preparation 23

[0584] This compound was prepared by a similar procedure to that ofExample 16.

[0585] Ethyl1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxylate.

[0586] IR (neat, cm⁻¹): 3600-2800, 1718, 1230, 1193, 1132, 1092

[0587] NMR (DMSO-d₆, δ): 0.90 (3H, d, J=6 Hz), 1.28 (3H, t, J=7 Hz),2.20-2.42 (2H, m), 2.80-3.30 (2H, m), 3.70-4.35 (4H, m), 5.14 (1H, d,J=5 Hz), 7.34 (1H, d, J=9 Hz), 7.40-7.95 (5H, m), 8.01 (1H, s), 8.14(1H, d, J=9 Hz)

[0588] MS: 386 (M+H)⁺

EXAMPLE 78

[0589] This compound was prepared by a similar procedure to that ofPreparation 1.

[0590]1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl)imidazole-4-carboxamide(78).

[0591] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1556, 1414, 1261, 1138,1090

[0592] NMR (DMSO-d₆, δ): 0.91 (3H, d, J=6 Hz), 2.20-2.42 (2H, m)2.75-3.30 (2H, m), 3.70-4.25 (2H, m), 5.11 (1H, d, J=5 Hz), 7.08 (1H,brs), 7.31 (1H, brs), 7.33 (1H, d, J=9 Hz), 7.40-7.95 (6H, m), 8.14 (1H,d, J=9 Hz)

[0593] MS: 357 (M+H)⁺

[0594] Preparation 24

[0595] This compound was prepared by a similar procedure to that ofPreparation 18.

[0596] Ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dichlorophenylthio)-3-pentyl]imidazole-4-carboxylate.

[0597] IR (neat, cm⁻¹): 3446, 2956, 2858, 1724, 1236, 1184, 1130, 1105,1027

[0598] NMR (CDCl₃, δ): −0.04 (3H, s), 0.02 (3H, s), 0.85 (9H, s) 1.03(3H, d, J=6 Hz), 1.39 (3H, t, J=7 Hz), 1.95-2.35 (2H, m), 2.40-2.97 (2H,m), 3.80-4.15 (2H, m), 4.37 (2H, q, J=7 Hz), 7.09 (1H, dd, J=8.2 Hz),7.35 (1H, d, J=8 Hz), 7.36 (1H, d, J=2 Hz), 7.50 (1H, s), 7.59 (1H, s)

[0599] MS: 517 (M+H)⁺ (³⁵Cl×2), 519 (M+H)⁺ (³⁵Cl-³⁷Cl)

[0600] Preparation 25

[0601] This compound was prepared by a similar procedure to that ofExample 16.

[0602] Ethyl1-[(2S,3R)-5-(3,4-dichlorophenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxylate.

[0603] IR (neat, cm⁻¹): 3600-2800, 1716, 1232, 1191, 1124, 1027

[0604] NMR (DMSO-d₆, δ): 0.85 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz),2.05-2.30 (2H, m), 2.65-2.90 (2H, m), 3.70-4.30 (4H, m), 5.14 (1H, d,J=5 Hz),7.24 (1H, dd, J=8.2 Hz), 7.50 (1H, d, J=2 Hz), 7.53 (1H, d, J=8Hz), 7.78 (1H, s), 7.92 (1H, s)

[0605] MS: 403 (M+H)⁺ (³⁵Cl×2), 405 (M+H)⁺ (³⁵Cl-³⁷Cl)

EXAMPLE 79

[0606] This compound was prepared by a similar procedure to that ofPreparation 1.

[0607]1-[(2S,3R)-5-(3,4-dichlorophenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(79).

[0608] IR (KBr, cm⁻¹): 3600-2800, 1660, 1594, 1456, 1414, 1263, 1126,1101

[0609] NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 2.05-2.30 (2H, m)2.65-2.90 (2H, m), 3.70-4.15 (2H, m), 5.13 (1H, d, J=5 Hz), 7.03 (1H,brs), 7.24 (1H, dd, J=8.2 Hz), 7.25 (1H, brs), 7.51 (1H, d, J=2 Hz),7.53 (1H, d, J=8 Hz), 7.70 (1H, s), 7.72 (1H, s)

[0610] MS: 374 (M+H)⁺ (³⁵Cl×2), 376 (M+H)⁺ (³⁵Cl-³⁷Cl)

[0611] Preparation 26

[0612] This compound was prepared by a similar procedure to that ofPreparation 18.

[0613] Ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dimethylphenylthio)-3-pentyl]imidazole-4-carboxylate.

[0614] IR (neat, cm⁻¹): 3448, 2954, 2858, 1724, 1234, 1184, 1130, 1105,1025

[0615] NMR (CDCl₃, δ)s: −0.06 (3H, s), 0.01 (3H, s), 0.84 (9H, s), 1.01(3H, d, J=6 Hz), 1.39 (3H, t, J=7 Hz), 1.95-2.30 (8H, m), 2.35-2.95 (2H,m), 3.80-4.20 (2H, m), 4.37 (2H, q, J=7 Hz), 7.00-7.15 (1H, m), 7.44(1H, s), 7.56 (1H, s)

[0616] MS: 477 (M+H)⁺

[0617] Preparation 27

[0618] This compound was prepared by a similar procedure to that ofExample 16.

[0619] Ethyl1-[(2S,3R)-5-(3,4-dimethylphenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxylate.

[0620] IR (neat, cm⁻¹): 3600-2800, 1716, 1230, 1192, 1124, 1027

[0621] NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz),2.00-2.30 (8H, m), 2.50-2.75 (2H, m), 3.65-4.30 (4H, m), 5.12 (1H, d,J=5 Hz), 6.90-7.10 (3H, m), 7.75 (1H, s), 7.89 (1H, s)

[0622] MS: 363 (M+H)⁺

EXAMPLE 80

[0623] This compound was prepared by a similar procedure to that ofPreparation 1.

[0624]1-[(2S,3R)-5-(3,4-dimethylphenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(80).

[0625] IR (KBr, cm⁻¹): 3600-2800, 1658, 1595, 1489, 1415, 1263, 1238,1126, 1093

[0626] NMR (DMSO-d₆, δ): 0.86 (3H, d, J=6 Hz), 2.00-2.25 (8H, m),2.50-2.75 (2H, m), 3.70-4.15 (2H, m), 5.10 (1H, d, J=5 Hz), 6.95-7.12(4H, m), 7.25 (1H, brs), 7.67 (2H, s)

[0627] MS: 334 (M+H)⁺

[0628] Preparation 28

[0629] To a suspension of (2R,3S)-2-amino-1,3-butanediol4-methylbenzenesulfonate (2.3 g) in nitromethane (32 mL) was addedtriethylamine (1.1 mL) and triethyl orthoformate (1.3 mL). The mixturewas stirred at 110° C. for 0.5 hour and cooled in an ice-bath. A mixtureof ethyl α-amino-α-cyanoacetate 4-methylbenzenesulfonate (2.0 g),triethylamine (1.0 mL) and acetonitrile (32 mL) was added to thereaction mixture, and the whole was stirred at 100° C. for 8 hours. Themixture was concentrated in vacuo and the residue was purified by columnchromatography on silica gel (gradient elution; 10:1 to 5:1chloroform-methanol containing 1% ammonium hydroxide) to give the crudeproduct, which was further purified by column chromatography on silicagel (gradient elution; 20:1 to 10:1 to 5:1 ethyl acetate-1% ammoniumhydroxide/methanol) to give ethyl5-amino-1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(1.0 g).

[0630] NMR (DMSO-d₆); 0.93 (3H, d, J=6 Hz), 1.23 (3H, t, J=7 Hz),3.8-4.1 (4H, m), 4.12 (2H, q, J=7 Hz), 4.9-5.0 (1H, m), 5.17 (1H, d, J=5Hz), 5.89 (2H, br s), 7.17 (1H, s)

[0631] Preparation 29

[0632] To a refluxing solution of isoamyl nitrite (1.5 mL) intetrahydrofuran (4.6 mL) was added a solution of ethyl5-amino-1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(0.92 g) in tetrahydrofuran (23 mL) dropwise over 45 minutes, and themixture was refluxed for 75 minutes. The reaction mixture was cooled toambient temperature and concentrated in vacuo. The residue was purifiedby column chromatography on silica gel (gradient elution; 10:1 to 5:1chloroform-1% ammonium hydroxide/methanol) to give ethyl1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(0.50 g).

[0633] NMR (DMSO-d₆); 0.88 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz),3.7-4.1 (4H, m), 4.21 (2H, q, J=7 Hz), 4.86 (1H, br s) 5.07 (1H, br s),7.72 (1H, d, J=1 Hz), 7.88 (1H, d, J=1 Hz)

[0634] Preparation 30

[0635] A mixture of ethyl1-[(1R,2S)-2-hydroxy-1-(hydroxymethyl)propyl]-1H-imidazole-4-carboxylate(0.88 g), 4-chlorophenylsulfonyl chloride (1.2 g) and pyridine (8.8 mL)was stirred at 4° C. for 3 days. The mixture was poured into water, andextracted with ethyl acetate. The extract was washed with brine, driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (gradient elution;50:1 to 25:1 chloroform-methanol) to give ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl)-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.89 g).

[0636] NMR (DMSO-d₆); 0.84 (3H, d, J=6 Hz), 1.27 (3H, t, J=7 Hz),3.8-4.0 (1H, m), 4.21 (2H, q, J=7 Hz), 4.3-4.4 (1H, m), 4.54 (2H, d, J=6Hz), 5.39 (1H, d, J=5 Hz), 7.6-7.9 (6H, m)

[0637] Preparation 31

[0638] A mixture of 3,4-dichlorophenol (1.0 g), cesium carbonate (2.1 g)and N,N-dimethylformamide (6 mL) was stirred at 80° C. for an hour. Tothe mixture was added a solution of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.52 g) in N,N-dimethylformamide (6 mL). The reaction mixture wasstirred at 80° C. overnight, cooled to ambient temperature and dilutedwith ethyl acetate. The precipitate was filtered off and the filtratewas successively washed with 1 N sodium hydroxide, water and brine,dried over anhydrous sodium sulfate, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (elution;25:1 chloroform-methanol) to give the crude product, which was furtherpurified by recrystallization from 1:1 n-hexane-ethyl acetate (4 mL) togive ethyl1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.25 g).

[0639] mp: 101-103° C.

[0640] NMR (DMSO-d₆); 0.96 (3H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz),4.0-4.1 (1H, m), 4.20 (2H, q, J=7 Hz), 4.4-4.6 (3H, m), 5.3-5.4 (1H, brm), 6.93 (1H, dd, J=2 Hz, 9 Hz), 7.24 (1H, d, J=2 Hz), 7.51 (1H, d, J=9Hz), 7.87 (1H, d, J=1 Hz), 8.03 (1H, s)

EXAMPLE 81

[0641] A mixture of ethyl1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.23 g), 28% ammonium hydroxide (12 mL) and 1,2-dimethoxyethane (6 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (gradient elution;20:1 to 10:1 chloroform-methanol) to give the product, which wasrecrystallized from 1:5 n-hexane-ethyl acetate (12 mL) to give1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxamide(81) (0.13 g).

[0642] mp: 115-121° C.

[0643] APCIMS: 344, 346 (M+H)

[0644] IR (KBr): 3328, 1664 cm⁻¹

[0645] NMR (DMSO-d₆); 0.95 (3H, d, J=6 Hz), 3.9-4.1 (1H, m), 4.3-4.6(3H, m), 5.34 (1H, d, J=5 Hz), 6.94 (1H, dd, J=2 Hz, 9 Hz), 7.05 (1H,br, s), 7.25 (1H, d, J=2 Hz), 7.26 (1H, br, s), 7.51 (1H, d, J=9 Hz),7.79 (1H, s), 7.80 (1H, s)

[0646] Preparation 32

[0647] This compound was prepared by a similar procedure to that ofPreparation 5.

[0648] 3′-hydroxy-1,1′-biphenyl-4-carbonitrile.

[0649] IR (KBr, cm⁻¹): 3500-2800, 2231, 1591, 1477, 1303, 1203, 839, 779

[0650] NMR (CDCl₃, δ): 5.10 (1H, s), 6.80-7.40 (4H, m), 7.55-7.80 (4H,m)

[0651] MS: 218 (M+Na)⁺

EXAMPLE 82

[0652] This compound was prepared by a similar procedure to that ofExample 15.

[0653]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(82).

[0654] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.60-4.35 (4H, m), 5.38 (1H, brs),6.75-7.00 (3H, m), 7.10-7.45 (3H, m), 7.55-7.80 (5H, m)

[0655] MS: 505 (M+H)⁺

EXAMPLE 83

[0656] This compound was prepared by a similar procedure to that ofExample 16.

[0657]1-{(2S,3R)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(83).

[0658] IR (KBr, cm⁻¹): 3600-2800, 2240, 1658, 1595, 1209, 839

[0659] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.60-4.30 (4H, m), 5.19 (1H, d, J=5 Hz), 6.85-7.45 (6H, m), 7.60-8.00(6H, m)

[0660] MS: 391 (M+H)⁺

[0661] Preparation 33

[0662] This compound was prepared by a similar procedure to that ofPreparation 5.

[0663] 4′-methyl-1,1′-biphenyl-3-ol.

[0664] IR (KBr, cm⁻¹): 3600-2800, 1595, 1481, 1296, 1192, 879, 775

[0665] NMR (CDCl_(3, δ):) 2.39 (3H, s), 4.83 (1H, s), 6.70-6.90 (1H, m),6.95-7.55 (7H, m)

[0666] MS: 183 (M−H)⁻

EXAMPLE 84

[0667] This compound was prepared by a similar procedure to that ofExample 15.

[0668]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(84).

[0669] NMR (CDCl₃, δ): 0.02 (3H, s), 0.06 (3H, s), 0.91 (9H, s) 1.10(3H, d, J=6 Hz), 2.00-2.65 (5H, m), 3.55-4.35 (4H, m), 5.32 (1H, brs),6.70-7.50 (10H, m), 7.64 (1H, s)

[0670] MS: 494 (M+H)⁺

EXAMPLE 85

[0671] This compound was prepared by a similar procedure to that ofExample 16.

[0672]1-{(2S,3R)-2-hydroxy-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(85).

[0673] IR (KBr, cm⁻¹): 3600-2800, 1658, 1595, 1479, 1410, 1263, 1090,781

[0674] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.60 (5H, m)3.55-4.35 (4H, m), 5.19 (1H, brs), 6.70-7.40 (8H, m), 7.57 (2H, d, J=8Hz), 7.71 (1H, s), 7.76 (1H, s)

[0675] MS: 380 (M+H)⁺

[0676] Preparation 34

[0677] This compound was prepared by a similar procedure to that ofPreparation 5.

[0678] 3-(6-chloro-3-pyridyl)phenol.

[0679] IR (KBr, cm⁻¹): 3500-2700, 1599, 1454, 1238, 1111

[0680] NMR (CDCl₃, δ): 5.85 (1H, s), 6.80-7.15 (3H, m), 7.25-7.50 (2H,m), 7.84 (1H, dd, J=8,3 Hz), 8.62 (1H, d, J=3 Hz)

[0681] MS: 204 (M−H)⁻ (³⁵Cl), 206 (M−H)⁻ (³⁷Cl)

EXAMPLE 86

[0682] This compound was prepared by a similar procedure to that ofExample 15.

[0683]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(6-chloro-3-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide(86).

[0684] NMR (CDCl₃, δ): 0.02 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.10(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.60-4.35 (4H, m), 5.35 (1H, brs),6.75-7.00 (3H, m), 7.11 (1H, d, J=8 Hz), 7.25-7.50 (3H, m), 7.64 (1H,s), 7.80 (1H, dd, J=8, 2 Hz), 8.56 (1H, d, J=2 Hz)

[0685] MS: 515 (M+H)⁺ (³⁵Cl), 517 (M+H)⁺ (³⁷Cl)

EXAMPLE 87

[0686] This compound was prepared by a similar procedure to that ofExample 16.

[0687]1-{(2S,3R)-5-[3-(6-chloro-3-pyridyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(87).

[0688] mp. 166-168° C.

[0689] IR (KBr, cm⁻¹): 3600-2800, 1652, 1592, 1456, 1236, 1105

[0690] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m)3.55-4.35 (4H, m), 5.19 (1H, d, J=5 Hz), 6.93 (1H, dd, J=8, 1 Hz), 7.03(1H, brs), 7.10-7.45 (4H, m), 7.59 (1H, d, J=8 Hz), 7.71 (1H, s), 7.75(1H, s), 8.14 (1H, dd, J=8, 2 Hz), 8.72 (1H, d, J=2 Hz)

[0691] MS: 401 (M+H)⁺ (³⁵Cl), 403 (M+H)⁺ (³⁷Cl)

[0692] Preparation 35

[0693] This compound was prepared by a similar procedure to that ofPreparation 5.

[0694] 2-(4-chlorophenyl)-6-methoxypyridine.

[0695] IR (KBr, cm⁻¹): 2976, 2943, 1579, 1464, 1254, 1020, 793

[0696] NMR (CDCl₃, δ): 4.03 (3H, s), 6.70 (1H, d, J=8 Hz), 7.20-7.70(4H, m), 7.90-8.05 (2H, m)

[0697] MS: 220 (M+H)⁺ (³⁵Cl), 222 (M+H)⁺ (³⁷Cl)

[0698] Preparation 36

[0699] To a stirred solution of 2-(4-chlorophenyl)-6-methoxypyridine(450 mg, 2.05 mmol) in chlorobenzene (5 ml) was added AlCl₃ (1.09 g,8.19 mmol) at room temperature. The resulting mixture was stirred underreflux for 10 min. The mixture was quenched with crushed ice under icebath temperature and partitioned between ethyl acetate (20 ml) andHClaq. The organic layer was washed with water and brine, dried(magnesium sulfate) and evaporated in vacuo.

[0700] The residue was triturated with hexane and dried under reducedpressure to give 6-(4-chlorophenyl)-2(1H)-pyridinone (382 mg, 91%) as awhite solid.

[0701] IR (KBr, cm⁻¹): 3600-2600, 1672, 1616, 1491, 1090, 791

[0702] NMR (DMSO-d₆, δ): 6.35-6.70 (2H, m), 7.35-7.75 (5H, m), 11.65(1H, br)

[0703] MS: 228 (M+Na)⁺ (³⁵Cl), 230 (M+Na)⁺ (³⁷Cl)

EXAMPLE 88

[0704] This compound was prepared by a similar procedure to that ofExample 15.

[0705]1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide(88).

[0706] NMR (CDCl₃, δ): 0.02 (3H, s), 0.04 (3H, s), 0.88 (9H, s), 1.07(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.85-4.65 (4H, m), 5.38 (1H, brs),6.64 (1H, d, J=8 Hz), 6.93 (1H, brs), 7.20-7.75 (6H, m), 7.87 (2H, d,J=8 Hz)

[0707] MS: 515 (M+H)⁺ (³⁵Cl), 517 (M+H)⁺ (³⁷Cl)

EXAMPLE 89

[0708] This compound was prepared by a similar procedure to that ofExample 16.

[0709]1-((2S,3R)-2-hydroxy-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide(89).

[0710] IR (KBr, cm⁻¹): 3600-2800, 1662, 1591, 1444, 1251, 1092, 1020,800

[0711] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.75-4.45 (4H, m), 5.18 (1H, d, J=5 Hz), 6.73 (1H, d, J=8 Hz), 7.06 (1H,brs), 7.27 (1H, brs), 7.45-7.90 (6H, m), 8.01 (2H, d, J=9 Hz)

[0712] MS: 401 (M+H)⁺ (³⁵Cl), 403 (M+H)⁺ (³⁷Cl)

EXAMPLE 90

[0713] This compound was prepared by a similar procedure to that ofExample 15.

[0714]1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide(90).

[0715] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.05-2.65 (2H, m), 3.60-4.35 (4H, m), 5.35 (1H, brs),6.70-7.00 (3H, m), 7.10 (1H, d, J=8 Hz), 7.25-7.50 (5H, m), 7.64 (1H, s)

EXAMPLE 91

[0716] This compound was prepared by a similar procedure to that ofExample 16.

[0717]1-{(2S,3R)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide(91).

[0718] IR (KBr, cm⁻¹): 3600-2800, 1657, 1591, 1558, 1236, 1092, 850, 795

[0719] NMR (DMSO-d₆, δ): 0.93 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.50-4.35 (4H, m), 5.19 (1H, d, J=5 Hz), 6.92 (1H, d, J=8, 1 Hz), 7.02(1H, brs), 7.15-7.45 (4H, m), 7.50-7.80 (5H, m)

[0720] MS: 434 (M+H)⁺ (³⁵Cl), 436 (M+H)⁺ (³⁷Cl)

EXAMPLE 92

[0721] This compound was prepared by a similar procedure to that ofExample 15.

[0722]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide(92).

[0723] NMR (CDCl₃, δ): 0.03 (3H, s), 0.06 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.10-2.65 (2H, m), 3.65-4.35 (7H, m), 5.34 (1H, brs),6.80-7.05 (5H, m), 7.44 (1H, s), 7.55-7.70 (3H, m)

[0724] MS: 484 (M+H)⁺

EXAMPLE 93

[0725] This compound was prepared by a similar procedure to that ofExample 16.

[0726]1-[(2S,3R)-2-hydroxy-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide(93).

[0727] IR (KBr, cm⁻¹): 3600-2800, 1633, 1259, 1219, 1157, 1029, 835

[0728] NMR (DMSO-d₆, δ): 0.95 (3H, d, J=6 Hz), 2.10-2.60 (2H, m),3.60-4.35 (7H, m), 5.20 (1H, d, J=5 Hz), 6.80-7.35 (6H, m), 6.60-7.85(4H, m)

[0729] MS: 370 (M+H)⁺

EXAMPLE 94

[0730] This compound was prepared by a similar procedure to that ofExample 15.

[0731]1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(94).

[0732] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.05-2.75 (2H, m), 3.60-4.35 (4H, m), 5.34 (1H, brs),6.89 (1H, d, J=2 Hz), 6.90 (1H, brs), 7.07 (1H, dd, J=9.2 Hz), 7.34-7.75(5H, m), 7.83 (1H, s)

[0733] MS: 532 (M+H)⁺ (⁷⁹Br), 534 (M+H)⁺ (⁸¹Br)

EXAMPLE 95

[0734] This compound was prepared by a similar procedure to that ofExample 16.

[0735]1-](2S,3R)-5-(7-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(95).

[0736] IR (KBr, cm⁻¹): 3600-2800, 1682, 1649, 1244, 1128, 1087, 837

[0737] (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.65 (2H, m), 3.60-4.35(4H, m), 5.20 (1H, d, J=5 Hz), 7.02 (1H, brs), 7.08-7.35 (3H, m), 7.43(1H, dd, J=8.2 Hz), 7.60-7.90 (4H, m), 8.02 (1H, d, J=2 Hz)

[0738] MS: 418 (M+H)⁺ (⁷⁹Br)

EXAMPLE 96

[0739] This compound was prepared by a similar procedure to that ofExample 15.

[0740]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-chloro-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide(96).

[0741] IR (KBr, cm⁻¹): 3600-2800, 1664, 1250, 1092, 835

[0742] NMR (CDCl₃, δ): 0.03 (3H, s), 0.07 (3H, s), 0.91 (9H, s), 1.11(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.60-4.35 (4H, m), 5.36 (1H, brs),6.89 (1H, d, J=2 Hz), 6.90 (1H, brs), 7.06 (1H, dd, J=9, 2 Hz),7.15-7.35 (1H, m), 7.43 (1H, s), 7.55-7.75 (4H, m)

[0743] MS: 488 (M+H)⁺ (³⁵Cl), 490 (M+H)⁺ (³⁷Cl)

EXAMPLE 97

[0744] This compound was prepared by a similar procedure to that ofExample 16.

[0745]1-[(2S,3R)-5-(7-chloro-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(97).

[0746] mp. 139-141° C.

[0747] IR (KBr, cm⁻¹): 3600-2800, 1662, 1620, 1246, 1211, 1082, 839

[0748] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.65 (2H, m),3.60-4.35 (4H, m), 5.20 (1H, d, J=5 Hz), 6.90-7.40 (5H, m), 7.60-7.95(5H, m)

[0749] MS: 374 (M+H)⁺ (³⁵Cl), 376 (M+H)⁺ (³⁷Cl)

EXAMPLE 98

[0750] This compound was prepared by a similar procedure to that ofExample 15.

[0751]1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-cyano-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide(98).

[0752] NMR (CDCl₃, δ): 0.04 (3H, s), 0.08 (3H, s), 0.92 (9H, s), 1.12(3H, d, J=6 Hz), 2.05-2.75 (2H, m), 3.60-4.35 (4H, m), 5.37 (1H, brs),6.91 (1H, brs), 7.01 (1H, d, J=2 Hz), 7.22 (1H, dd, J=9.2 Hz), 7.45 (1H,s), 7.47 (1H, d, J=9 Hz), 7.65 (1H, s), 7.74 (1H, d, J=9 Hz), 7.82 (1H,d, J=9 Hz), 8.04 (1H, s)

[0753] MS: 479 (M+H)⁺

EXAMPLE 99

[0754] This compound was prepared by a similar procedure to that ofExample 16.

[0755]1-[(2S,3R)-5-(7-cyano-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide(99).

[0756] IR (KBr, cm⁻¹): 3600-2800, 2225, 1658, 1599, 1263, 1217, 1126,1092, 842

[0757] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.65 (2H, m),3.60-4.35 (4H, m), 5.20 (1H, brs), 7.05 (1H, brs), 7.15-7.45 (3H, m),7.60 (1H, dd, J=8,1 Hz), 7.70-8.10 (4H, m), 8.36 (1H, s)

[0758] MS: 365 (M+H)⁺

EXAMPLE 100

[0759] This compound was prepared by a similar procedure to that ofExample 15.

[0760]1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-3-pentyl)imidazole-4-carboxamide(100).

[0761] IR (KBr, cm⁻¹): 3600-2800, 1666, 1592, 1481, 1261, 1145, 1095,835

[0762] NMR (CDCl₃, δ): 0.04 (3H, s), 0.07 (3H, s), 0.92 (9H, s), 1.12(3H, d, J=6 Hz), 2.05-2.70 (2H, m), 3.60-4.35 (4H, m), 5.35 (1H, brs),6.80-7.05 (3H, m), 7.35-7.70 (5H, m), 8.12 (2H, d, J=9 Hz)

[0763] MS: 555 (M+H)⁺ (³⁵Cl), 557 (M+H)⁺ (³⁷Cl)

EXAMPLE 101

[0764] This compound was prepared by a similar procedure to that ofExample 16.

[0765]1-((2S,3R)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-2-hydroxy-3-pentyl)imidazole-4-carboxamide(101).

[0766] IR (KBr, cm⁻¹): 3600-2800, 1654, 1617, 1481, 1267, 1146, 1053,827

[0767] NMR (DMSO-d₆, δ): 0.94 (3H, d, J=6 Hz), 2.10-2.70 (2H, m),3.60-4.35 (4H, m), 5.20 (1H, d, J=5 Hz), 6.80-7.45 (4H, m), 7.50-7.90(5H, m), 8.12 (2H, d, J=8 Hz)

[0768] MS: 441 (M+H)⁺ (³⁵Cl), 443 (M+H)⁺ (³⁷Cl)

REFERENCE EXAMPLE 1

[0769] Under N₂, a cold (−75° C.) solution of oxalyl chloride (285 mg,2.24 mmol) in CH₂Cl₂ (10 ml) was treated with DMSO (0.215 ml, 3.03 mmol)and stirred for 10 min. A solution of ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-hydroxy-3-pentyl]imidazole-4-carboxylate(400 mg, 1.12 mmol) in CH₂Cl₂ (5 ml) was slowly added, the resultingmixture was stirred for 50 min at −75 to −45° C. and finally treatedwith triethylamine (0.59 ml). The reaction mixture was allowed to warmto 0° C., hydrolyzed with water (10 ml) and extracted with CH₂Cl₂ (20ml×2). The combined organic layers were dried over sodium sulfate andevaporated in vacuo. The residue was purified by silica gel (13 g)chromatography eluting with chloroform/methanol (100:1) to give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-oxo-3-pentyl]imidazole-4-carboxylate(370 mg, 93%) as a colorless syrup.

[0770] IR (neat, cm⁻¹): 3435, 2958, 2860, 1722, 1709, 1547, 1238, 1092,1034

[0771] NMR (CDCl_(3, δ): −)0.01 (3H, s), 0.04 (3H, s), 0.91 (9H, s),1.09 (3H, d, J=6 Hz), 1.38 (3H, t, J=7 Hz), 3.00-3.13 (1H, m), 3.85-4.60(5H, m), 7.56 (1H, s), 7.64 (1H, s)

[0772] MS: 377 (M+Na)⁺

REFERENCE EXAMPLE 2

[0773] Under N₂, to a suspension of 2-naphthylmethyltriphenylphosphoniumbromide (355 mg, 0.733 mmol) in THF (8 ml) and DMSO (4 ml) was addedt-BuOK at room temperature. After stirring for 20 min., the mixture wascooled to 5-7° C. in an ice bath and then ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-oxo-3-pentyl]imidazole-4-carboxylate(130 mg, 0.367 mmol) in THF (6 ml) was added. The mixture was stirredfor 1 h at room temperature. The reaction mixture was poured into water(25 ml) and extracted with ethyl acetate. The organic layer was washedwith brine, dried (sodium sulfate) and evaporated in vacuo. The residuewas purified by silica gel (15 g) chromatography eluting withchloroform/methanol (100:1 to 50:1) to give ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-6-(2-naphthyl)-5-hexen-3-yl]]imidazole-4-carboxylate(130 mg, 74.1%).

[0774] NMR (CDCl₃, δ): −0.03-0.08 (6H, m), 0.70-1.45 (15H, s), 2.60-3.20(2H, m), 3.80-4.40 (4H, m), 5.35-6.75 (2H, m), 7.20-7.90 (9H, m)

[0775] MS: 479 (M+H)⁺

REFERENCE EXAMPLE 3

[0776] This compound was prepared by a similar procedure to that ofPreparation 3.

[0777] Ethyl1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-6-(2-naphthyl)-3-hexyl]imidazole-4-carboxylate.

[0778] IR (neat, cm⁻¹): 3375, 2941, 2860, 1724, 1232, 1182, 1124, 1031

[0779] NMR (CDCl₃, δ): −0.05 (3H, s), 0.00 (3H, s), 0.83 (9H, s), 0.97(3H, d, J=6 Hz), 1.39 (3H, t, J=7 Hz), 1.60-2.15 (4H, m), 2.77 (2H, t,J=7 Hz), 3.75-4.00 (2H, m), 4.36 (2H, q, J=7 Hz), 7.15-7.60 (6H, m),7.70-7.87 (3H, m)

[0780] MS: 481 (M+H)⁺

REFERENCE EXAMPLE 4

[0781] This compound was prepared by a similar procedure to that ofExample 16.

[0782] Ethyl1-[(2S,3R)-2-hydroxy-6-(2-naphthyl)-3-hexyl]imidazole-4-carboxylate.

[0783] IR (neat, cm⁻¹): 3600-2800, 1718, 1234, 1188, 1124, 1028

[0784] NMR (DMSO-d₆, δ): 0.87 (3H, d, J=6 Hz), 1.15-1.65 (5H, m),1.70-2.10 (2H, m), 2.60-2.85 (2H, m), 3.65-4.10 (2H, m), 4.20 (2H, q,J=7 Hz), 5.07 (1H, d, J=5 Hz), 7.20-7.50 (3H, m), 7.61 (1H, s),7.70-7.95 (5H, m)

[0785] MS: 367 (M+H)⁺

REFERENCE EXAMPLE 5

[0786] This compound was prepared by a similar procedure to that ofPreparation 1.

[0787]1-[(2S,3R)-2-hydroxy-6-(2-naphthyl)-3-hexyl]imidazole-4-carboxamide.

[0788] IR (KBr, cm⁻¹): 3600-2800, 1658, 1593, 1412, 1261, 1240, 1124,1093

[0789] NMR (DMSO-d₆, δ): 0.87 (3H, d, J=6 Hz), 1.15-1.60 (2H, m),1.70-2.10 (2H, m), 2.55-2.85 (2H, m), 3.65-4.10 (2H, m), 5.06 (1H, d,J=5 Hz), 7.02 (1H, brs), 7.24 (1H, brs), 7.31 (1H, d, J=8 Hz), 7.35-7.90(8H, m)

[0790] MS: 338 (M+H)⁺

REFERENCE EXAMPLE 6

[0791] A mixture of 2-naphthol (1.4 g), cesium carbonate (3.2 g) andN,N-dimethylformamide (10 mL) was stirred at 60° C. for half an hour. Tothe mixture was added a solution of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl]oxy}methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.81 g) in N,N-dimethylformamide (10 mL). The reaction mixture wasstirred at 60° C. for 4 hours, cooled to ambient temperature and dilutedwith ethyl acetate. The precipitate was filtered off and the filtratewas succesively washed with 1 N sodium hydroxide, water and brine, driedover anhydrous sodium sulfate, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel (elution; 25:1chloroform-methanol) to give the crude product, which was furtherpurified by recrystallization from ethanol to give ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl]propyl}-1H-imidazole-4-carboxylate(0.13 g).

[0792] The mother liquor and the mixed fractions were combined andpurified by column chromatography on silica gel (gradient elution; 50:1to 25:1 chloroform-methanol) to give the additional product (0.14 g).

[0793] mp: 191-192° C.

[0794] NMR (DMSO-d₆); 1.00 (3H, d, J=6 Hz), 1.25 (3H, t, J=7 Hz),4.0-4.1 (1H, m), 4.20 (2H, q, J=7 Hz), 4.4-4.7 (3H, m), 5.39 (1H, d, J=5Hz), 7.0-7.2 (1H, m), 7.3-7.5 (3H, m), 7.7-7.9 (3H, m), 7.91 (1H, d, J=1Hz), 8.08 (1H, d, J=1 Hz)

REFERENCE EXAMPLE 7

[0795] A mixture of ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl]propyl}-1H-imidazole-4-carboxylate(0.25 g), 28% ammonium hydroxide (14 mL) and 1,2-dimethoxyethane (7 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (gradient elution;20:1 to 10:1 chloroform-methanol) to give the product, which wasrecrystallized from 5:1 ethyl acetate-ethanol (6 mL) to give ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthyloxy)methyl)propyl}-1H-imidazole-4-carboxamide(0.12 g).

[0796] mp: 162-164° C.

[0797] APCIMS: 326 (M+H)

[0798] IR (KBr): 3318, 1666 cm⁻¹

[0799] NMR (DMSO-d₆); 1.00 (3H, d, J=6 Hz), 3.9-4.2 (1H, m), 4.4-4.7(3H, m), 5.38 (1H, d, J=5 Hz), 7.0-7.2 (1H, m), 7.06 (1H, br, s),7.2-7.5 (4H, m), 7.28 (1H, br, s), 7.7-7.9 (4H, m)

[0800] Preparation 37

[0801] To a mixture of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl)}oxy)methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.32 g), 2-naphthalenethiol (0.19 g) and N,N-dimethylformamide (5 mL)was added cesium carbonate (0.38 g) and the reaction mixture was stirredat ambient temperature overnight. The mixture was partitioned betweenethyl acetate and water. The organic layer was separated, washed withbrine, dry over Na₂SO₄, and concentrated in vacuo. The residue waspurified by column chromatography on silica gel (elution; 25:1chloroform-methanol) to give the product, which was triturated with 1:1n-hexane-ethyl acetate (10 mL) to give ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.19 g).

[0802] mp: 117-120° C.

[0803] NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 1.24 (3H, t, J=7 Hz),3.5-4.1 (3H, m), 4.1-4.3 (1H, m), 4.17 (2H, q, J=7 Hz), 5.35 (1H, d, J=5Hz), 7.3-7.6 (3H, m), 7.7-7.9 (5H, m), 7.98 (1H, s)

EXAMPLE 102

[0804] A mixture of ethyl1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.18 g), 28% ammonium hydroxide (20 mL) and 1,2-dimethoxyethane (10 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (elution; 10:1chloroform-1% ammonium hydroxide/methanol) to give the product, whichwas recrystallized from 3:7 n-hexane-ethyl acetate (10 mL) to give1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamide(102) (90 mg).

[0805] mp: >108° C. (dec.)

[0806] APCIMS: 342 (M+H)

[0807] NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 3.4-4.2 (4H, m), 5.34 (1H,d, J=5 Hz), 7.05 (1H, br, s), 7.26 (1H, br, s), 7.4-7.6 (3H, m), 7.71(1H, s), 7.7-7.9 (5H, m)

[0808] Preparation 38

[0809] A mixture of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl)-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.25 g), 1-naphthalenethiol (0.14 g), cesium carbonate (0.30 g) andN,N-dimethylformamide (5 mL) was stirred at ambient temperature for 1.5hours. The mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, washed with brine, dried over Na₂SO₄, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (gradient elution; 50:1 to 25:1 chloroform-methanol) togive the product, which was triturated with 10:1 diisopropylether-ethanol (11 mL) to give ethyl1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.19 g).

[0810] mp: 110-115° C.

[0811] NMR (DMSO-d₆); 0.87 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz),3.5-4.0 (3H, m), 4.0-4.3 (1H, m), 4.20 (2H, q, J=7 Hz), 5.31 (1H, d, J=5Hz), 7.4-7.6 (4H, m), 7.78 (1H, s), 7.8-7.9 (1H, m), 7.9-8.2 (2H, m),7.97 (1H, d, J=1 Hz)

EXAMPLE 103

[0812] A mixture of ethyl1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxylate(0.18 g), 28% ammonium hydroxide (5 mL) and 1,2-dimethoxyethane (10 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (gradient elution;15:1 to 10:1 chloroform-methanol) to give1-[(2R,3S)-1-(1-naphthylthio)-3-hydroxy-2-butyl]imidazol-4-carboxamide.The product was dissolved in MeOH (5 mL) and treated with a solution of4 N hydrogen chloride in ethyl acetate (1 mL). The mixture wasconcentrated in vacuo and the residue was recrystallized from 5:1 ethylacetate-methanol (6 mL) to give1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamidehydrochloride (103) (0.11 g).

[0813] mp: >168° C. (dec.)

[0814] MS: 342 (M (free)+H), 364 (M (free)+Na)

[0815] NMR (DMSO-d₆); 1.00 (3H, d, J=6 Hz), 3.3-4.0 (2H, m), 4.0-4.1(1H, m), 4.3-4.5 (1H, m), 4.8-6.6 (1H, br m), 7.4-7.7 (5H, m), 7.82 (1H,br, s), 7.8-8.2 (3H, m), 8.20 (1H, br, s), 8.29 (1H, d, J=1 Hz), 9.09(1H, s)

[0816] Preparation 39

[0817] A mixture of ethyl1-[(1R,2S)-1-({[4-chlorophenyl]sulfonyl}oxy)methyl]-2-hydroxypropyl]-1H-imidazole-4-carboxylate(0.30 g), 2,3-dichlorobenzenethiol (0.19 g), cesium carbonate (0.36 g)and N,N-dimethylformamide (5 mL) was stirred at ambient temperature for2 hours. The mixture was partitioned between ethyl acetate and water.The organic layer was separated, washed with brine, dried over Na₂SO₄,and concentrated in vacuo. The residue was purified by columnchromatography on silica gel (gradient elution; 50:1 to 25:1chloroform-methanol) to give the product, which was triturated with 1:1diisopropyl ether-ethyl acetate (10 mL) to give ethyl1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.18 g).

[0818] mp: 141-143° C.

[0819] NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 1.26 (3H, t, J=7 Hz),3.5-4.3 (4H, m), 4.20 (2H, q, J=7 Hz), 5.43 (1H, d, J=5 Hz), 7.3-7.5(3H, m), 7.81 (1H, s), 8.01 (1H, d, J=1 Hz)

EXAMPLE 104

[0820] A mixture of ethyl1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxylate(0.17 g), 28% ammonium hydroxide (10 mL) and 1,2-dimethoxyethane (20 mL)was heated at 100° C. in the stainless steel bottle for 24 hours. Aftercooling, the reaction mixture was concentrated in vacuo and the residuewas purified by column chromatography on silica gel (elution; 10:1chloroform-1% ammonium hydroxide/methanol) to give the product, whichwas recrystallized from 1:1 n-hexane-ethyl acetate (10 mL) to give1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxamide(104) (0.10 g).

[0821] mp: >120° C. (dec.)

[0822] APCIMS: 359, 361 (M+H)

[0823] IR (KBr): 3322, 1662 cm⁻¹

[0824] NMR (DMSO-d₆); 0.92 (3H, d, J=6 Hz), 3.4-4.2 (4H, m), 5.42 (1H,d, J=5 Hz), 7.06 (1H, br, s), 7.27 (1H, br, s), 7.3-7.5 (3H, m), 7.74(1H, s), 7.80 (1H, s)

[0825] Industrial Applicability

[0826] Novel imidazole compounds having pharmaceutical activity such asADA inhibiting activity are provided. These compounds are useful inimmunomodulation, especially immunosuppression, antiinflammation andtreatment and prevention of various diseases for which Ado is effective.Such diseases include autoimmune diseases, inflammation, organ or tissueallo- or xeno-transplant rejection, leukemias, and diseases that arisefrom, or are aggravated by, insufficient blood flow through a particularorgan or portion thereof. These compounds or their prodrugs or salts canbe administered to patients in need of the treatment in an effectiveamount to elevate adenosine concentration.

1. A compound of the formula

wherein R¹ is aryl or heterocyclic group which is optionally substitutedwith substituent(s); R² is lower alkyl; R³ is hydroxy or protectedhydroxy; -A- is lower alkylene; and —X— is —O— or —S—; provided thatwhen —X— is —O—, then R¹ is aryl which is substituted withsubstituent(s), or heterocyclic group which is optionally substitutedwith substituent(s), its prodrug, or their salt.
 2. The compoundaccording to claim 1, wherein R¹ is (1) aryl optionally substituted withsubstituent(s) selected from the group consisting of lower alkyl,halogen, optionally substituted aryl, optionally substitutedheterocyclic group, lower alkoxy, and cyano, (2) condensed heterocyclicgroup optionally substituted with substituent(s) selected from the groupconsisting of lower alkyl, optionally substituted aryl, andaryl(lower)alkyl, or (3) unsaturated heteromonocyclic group containing 1to 4 nitrogen atoms which is optionally substituted with optionallysubstituted aryl.
 3. The compound according to claim 2, wherein thesubstituent(s) of optionally substituted aryl and optionally substitutedheterocyclic group are selected from the group consisting of loweralkyl, halo(lower)alkyl, lower alkoxy, halogen, aryl, aryl(lower)alkyl,and cyano.
 4. The compound according to claim 1, wherein -A- ismethylene or ethylene.
 5. The compound according to claim 1, wherein R²is methyl.
 6. The compound according to claim 1, which is a compoundselected from the group consisting of: (1)1-[(2S,3R)-2-benzyloxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(2)1-[(2S,3R)-2-hydroxy-5-(6-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(3)1-[(2S,3R)-2-benzyloxy-5-(3,4-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide;(4)1-[(2S,3R)-5-(3,4-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(5)1-[(2S,3R)-2-benzyloxy-5-(2-dibenzofuranyloxy)-3-pentyl]imidazole-4-carboxamide;(6)1-[(2S,3R)-5-(2-dibenzofuranyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(7)1-[(2S,3R)-2-benzyloxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide;(8)1-[(2S,3R)-2-hydroxy-5-(2-methyl-5-benzothiazolyloxy)-3-pentyl]imidazole-4-carboxamide;(9)1-[(2S,3R)-2-benzyloxy-5-(2-fluorenyloxy)-3-pentyl]imidazole-4-carboxamide;(10)1-[(2S,3R)-5-(2-fluorenyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(11)1-[(2S,3R)-2-benzyloxy-5-(2,3-dichlorophenoxy)-3-pentyl]imidazole-4-carboxamide;(12)1-[(2S,3R)-5-(2.3-dichlorophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(13)1-[(2S,3R)-2-benzyloxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(14)1-[(2S,3R)-2-hydroxy-5-(7-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(15)1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(16)1-[(2S,3R)-5-(6-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(17)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3,4-dimethylphenoxy)-3-pentyl]imidazole-4-carboxamide;(18)1-[(2S,3R)-5-(3,4-dimethylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(19)1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide(19); (20)1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(21)1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(22)1-[(2S,3R)-5-(1,1′-biphenyl-2-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(23)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(24)1-[(2S,3R)-2-hydroxy-5-(3-isoquinolyloxy)-3-pentyl]imidazole-4-carboxamide;(25)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide;(26)1-{(2S,3R)-2-hydroxy-5-[1-methyl-2-(2-phenylethyl)-1H-indol-5-yloxy]-3-pentyl}imidazole-4-carboxamide;(27)1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(28)1-[(2S,3R)-5-(1,1′-biphenyl-4-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(29)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(3-tert-butylphenoxy)-3-pentyl]imidazole-4-carboxamide;(30)1-[(2S,3R)-5-(3-tert-butylphenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(31)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(32) 1-{(2S,3R)-2-hydroxy-5-[3-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide; (33)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(34)1-{(2S,3R)-2-hydroxy-5-[2-(2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(35)1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(36)1-{(2S,3R)-5-[3-(2-benzylthiazol-4-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(37)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-phenylthiazol-4-yl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(38)1-{(2S,3R)-2-hydroxy-5-[3-(2-phenylthiazol-4-yl)phenoxy]3-pentyl}imidazole-4-carboxamide;(39)1-[(2S,3R)-5-(3-bromophenoxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(40)1-[(2S,3R)-5-(3-bromophenoxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(41)1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(42)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(43)1-{(2S,3R)-2-hydroxy-5-[3-(4-morpholinyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(44)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-chloro-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(45) 1-{(2 S,3R)-5-[3-(5-chloro-2-thienyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide; (46)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(47)1-{(2S,3R)-2-hydroxy-5-[3-(5-methyl-2-thienyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(48)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(49)1-[(2S,3R)-2-hydroxy-5-(2-quinolyloxy)-3-pentyl]imidazole-4-carboxamide;(50)1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(51)1-{(2S,3R)-5-[3-(2-benzoxazolyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(52)1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(53) 1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(54)1-{2S,3R}-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-(tert-butyldimethylsilyloxy)-3-pentyl}imidazole-4-carboxamide;(55) 1-{(2S,3R)-5-[3-(1H-benzimidazol-2-yl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(56)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(57)1-{(2S,3R)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(58)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(59)1-{(2S,3R)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(60)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(61)1-{(2S,3R)-5-[(2′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(62)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(63)1-{(2S,3R)-2-hydroxy-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(64)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(65)1-{(2S,3R)-2-hydroxy-5-[(3′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(66)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(2-methoxy-5-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(67)1-{(2S,3R)-2-hydroxy-5-[3-(6-methoxy-3-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(68)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide;(69)1-{(2S,3R)-2-hydroxy-5-[(6-phenyl-2-pyridyl)oxy]-3-pentyl}imidazole-4-carboxamide;(70)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(71)1-{(2S,3R)-5-[(4′-fluoro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(72)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]oxy}-3-pentyl]imidazole-4-carboxamide;(73)1-[(2S,3R)-2-hydroxy-5-{[4′-(trifluoromethyl)-1,1′-biphenyl-3-yl]oxy}-3-pentyl]imidazole-4-carboxamide;(74)1-{(2S,3R)-2-hydroxy-5-[3-(1H-pyrrol-1-yl)-2-naphthyloxy]-3-pentyl}imidazole-4-carboxamide;(75)1-[(2S,3R)-2-hydroxy-5-(1-methyl-1H-indol-5-yl)oxy-3-pentyl]imidazole-4-carboxamide;(76)1-[(2S,3R)-2-hydroxy-5-(2-naphthylthio)-3-pentyl]imidazole-4-carboxamide;(77)1-[(2S,3R)-2-hydroxy-5-(1-naphthylthio)-3-pentyl]imidazole-4-carboxamide;(78)1-[(2S,3R)-2-hydroxy-5-(2-quinolylthio)-3-pentyl]imidazole-4-carboxamide;(79)1-[(2S,3R)-5-(3,4-dichlorophenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(80)1-[(2S,3R)-5-(3,4-dimethylphenylthio)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(81)1-{(1R,2S)-1-[(3,4-dichlorophenoxy)methyl]-2-hydroxypropyl}-1H-imidazole-4-carboxamide;(82)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide; (83)1-{(2S,3R)-5-[(4′-cyano-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(84)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(85)1-{(2S,3R)-2-hydroxy-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(86)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[3-(6-chloro-3-pyridyl)phenoxy]-3-pentyl}imidazole-4-carboxamide;(87)1-{(2S,3R)-5-[3-(6-chloro-3-pyridyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(88)1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide;(89)1-((2S,3R)-2-hydroxy-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide;(90)1-{(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(91)1-{(2S,3R)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(92)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(93)1-[(2S,3R)-2-hydroxy-5-(7-methoxy-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(94)1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-(tert-butyldimethylsilyloxy)-3-pentyl]imidazole-4-carboxamide;(95)1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(96)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-chloro-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(97)1-[(2S,3R)-5-(7-chloro-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(98)1-[(2S,3R)-2-(tert-butyldimethylsilyloxy)-5-(7-cyano-2-naphthyloxy)-3-pentyl]imidazole-4-carboxamide;(99)1-[(2S,3R)-5-(7-cyano-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(100)1-((2S,3R)-2-(tert-butyldimethylsilyloxy)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-3-pentyl)imidazole-4-carboxamide;(101)1-((2S,3R)-5-{[2-(4-chlorophenyl)-1,3-benzoxazol-6-yl]oxy}-2-hydroxy-3-pentyl)imidazole-4-carboxamide;(102)1-{(1R,2S)-2-hydroxy-1-[(2-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamide;(103) 1-{(1R,2S)-2-hydroxy-1-[(1-naphthylthio)methyl]propyl}-1H-imidazole-4-carboxamidehydrochloride; and (104)1-{(1R,2S)-1-{[(2,3-dichlorophenyl)thio]methyl}-2-hydroxypropyl}-1H-imidazole-4-carboxamide.7. The compound according to claim 1, which is a compound selected fromthe group consisting of: (20)1-[(2S,3R)-5-(1,1′-biphenyl-3-yloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;(41)1-{(2S,3R)-5-[3-(2-benzo[b]thiophenyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(53)1-{(2S,3R)-5-[3-(2-benzofuranyl)phenoxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(57)1-{(2S,3R)-5-[(4′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(59)1-{(2S,3R)-5-[(3′-chloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(63)1-{(2S,3R)-2-hydroxy-5-[(4′-methoxy-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(85)1-{(2S,3R)-2-hydroxy-5-[(4′-methyl-1,1′-biphenyl-3-yl)oxy]-3-pentyl}imidazole-4-carboxamide;(89)1-((2S,3R)-2-hydroxy-5-{[6-(4-chlorophenyl)-2-pyridyl]oxy}-3-pentyl)imidazole-4-carboxamide;(91)1-{(2S,3R)-5-[(3′,5′-dichloro-1,1′-biphenyl-3-yl)oxy]-2-hydroxy-3-pentyl}imidazole-4-carboxamide;(95)1-[(2S,3R)-5-(7-bromo-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide;and (97)1-[(2S,3R)-5-(7-chloro-2-naphthyloxy)-2-hydroxy-3-pentyl]imidazole-4-carboxamide.8. A pharmaceutical composition comprising the compound of claim 1 as anactive ingredient and a pharmaceutically acceptable, substantiallynon-toxic carrier or excipient.
 9. A pharmaceutical composition havingan adenosine deaminase inhibiting activity, which comprises the compoundof claim 1 as an active ingredient and a pharmaceutically acceptable,substantially non-toxic carrier or excipient.
 10. A method forinhibiting adenosine deaminase, which comprises administering thecompound of claim 1 to a mammal in need of the compound.
 11. A methodfor treating and/or preventing diseases for which adenosine iseffective, which comprises administering the compound of claim 1 to amammal in need of the compound.
 12. A method for treating and/orpreventing autoimmune diseases; inflammatory conditions; organ or tissueallo- or xeno-transplant rejection; various leukemias; or diseases thatarise from, or are aggravated by, insufficient blood flow through aparticular organ or portion thereof, which comprises administering thecompound of claim 1 to a mammal in need of the compound.
 13. Use of thecompound of claim 1 for preparing a medicament for treating and/orpreventing autoimmune diseases; inflammatory conditions; organ or tissueallo- or xeno-transplant rejection; various leukemias; or diseases thatarise from, or are aggravated by, insufficient blood flow through aparticular organ or portion thereof.
 14. A process for producing thecompound of claim 1, the process comprising any of the following steps(1) to (3): (1) reacting a compound of formula (II) R¹—OH   (II) whereinR¹ is as defined above, with a compound of formula (III)

wherein R², R³, and -A- are as defined above, and X¹ is hydroxy or aleaving group, provided that R³ is not hydroxy; (2) reacting a compoundof formula (I-1)

wherein R¹, R², and -A- are as defined above, and R′ is hydroxyprotective group, with a deprotecting agent; or (3) reacting a compoundof formula (IV)

wherein R¹, R², R³, -A-, and —X— are as defined above, with aqueousammonia solution.